FORM 2

THE PATENTS ACT-1970
COMPLETE SPECIFICATION
(See section 1O)
AN IMPROVED SITE SPECIFIC DRUG DELIVERY
SYSTEM
EMCURE PHARMACEUTICALS LTD., T-184, MIDC, Bhosari Pune-411026 (India), a Company registered under the Company Act- 1956
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:



1

This invention relates to an improved site specific drug delivery system. More particularly it relates to such a system designated and referred hereinafter as Colon Drug Delivery System (CDDS) comprising a Tablet-In-Tablet The drug delivery system provided by the present invention is useful for releasing the drug specifically at its site of action. Still more particularly it relates to delivery of drugs such as Metronidazole at the colon site and nearby affected organs.
Oral injestion is the most convenient and commonly used method of drug delivery. More than 50% of drug delivery systems available in the market are oral drug delivery system. These systems have obvious advantage of ease of administration and patient's expectance. The ideal drug delivery system should possess two main prosperities
1. It should be a single dose for the whole duration of treatment.
2. It should deliver the active drug directly at the site of the action.
Colon specific drug delivery is recognised to be advantageous in the treatment of Protozoal infection especially in amoebiasis is usually is tropical diseases having worldwide occurrence
Metronidazole, chemically, 2-methyl-5-nitro imidazole-1-ethanol is most useful of a vast number of antiprotozal nitro imidazole derivatives that have been used through out the world.
Metronidazole has been used since the 1960s in the treatment of various infections; it is primarily active against obligate anaerobic microorganisms, both bacteria and protozoa. It is available as tablets, capsules, oral suspension, topical cream/gel, suppositories and intravenous infusions.
Metronidazole is an antimicrobial that is primarily active against obligate anaerobic microorganisms, both bacteria and protozoa. The mechanism of action of
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metronidazole is believed to involve 4 phases: (a) entry into the bacterium cell (b) reduction of the 5- nitro group (c) cytotoxic effect of the reduced product (d) liberation of inactive end products. It is the formation of the reduced intermediate that is lethal to the microorganisms. The intracellular %get for these intermediates could be RNA, DNA or cellular proteins of the organises (Muller M. Mode of action of metronidazole on anaerobic bacteria and protozoa. Surgery 1983; 93: 165-71.) Metronidazole has demonstrated activity against protozoa such as G. lamblia (affecting primarily upper 1/3 rd of intestine) and £. histolytica (affecting colon). In addition it shows bactericidal activity against gram negative obligate anaerobic bacteria such as Bacteroides spp, Fusobacterium Spp, Helicobacter, actinobacillus amu1 prewllr amu1 grairr pusiilve dacerrar which include peptostretococci Clostridium perfringens and C. difficile (Freeman CD, Klutman NE, Lamp KC. Metronidazole: A Therapeutic review and update. Drugs 1997; 54(5): 679-708. Metronidazole has excellent oral bioavailability Approaching 100%. Peak plasma concentrations are seen within 0.25 to 4 hours. The protein binding of metronidazole is <20%. It has good cellular penetration and distributes well into a variety of tissue and fluids.
Metronidazole is extensively metabolised by the liver to 5 metabolites. The hydroxy metabolite has biological activity of 30 to 65% and a longer elimination half-life than the parent compound. The majority of metronidazole and its metabolites are excreted in urine and faeces, with less than 12% excreted unchanged in urine. The pharmacokinetics of metronidazole are unaffected by acute or chronic renal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age, pregnancy or enteric disease Lamp KC, Freeman CD, Klutman NE, Lacy MK. Pharmacokinetics and
3

pharmacodynamics of the nitroimidazole antimicrobials. (Clin Pharmacokinet 1999 May;36(5):353-73)
Metronidazole has been used in the treatment of amoebiasis, trichomoniasis, bacterial vaginosis, acute necrotising ulcerative gingivitis, anaerobic bacterial infections and peptic ulcer disease. (Parfitt K. Martindale: the Complete Drug reference. 32nd edition, Pharamceutical Press: London, 1999:585-88.). It has been found to be useful in the treatment of perianal Crohn's disease especially limited to the colon. (Sack DM, Peppercorn MA. Drug therapy of inflammatory bowel disease. Pharmacotherapy 1983; 3(3): 158-76)
Metronidazole has been successfully used in the treatment of anaerobic infections of the chest, head, gastrointestinal and female genitourinary tract, and of anaerobic septicaemia and bacteraemia. It is the most active agent available against obligate anaerobes and is of major value in the treatment of serious infections due to these organisms. (Brogden RN, Heel RC, Speight TM, Avery GS. Metronidazole in anaerobic infections: a review of its activity, pharmacokinetics and therapeutic use. Drugs 1978 Nov;16(5):387-417). It is the treatment of choice for intestinal amoebiasis and amoebic liver abscesses (Bassily S, Farid Z, el-Masry NA, Mikhail EM Treatment of intestinal E. histolytica and G. lamblia with metronidazole, tinidazole and ornidazole: a comparative study. J Trap Med Hyg 1987 Feb;90(l):9-12. Green PH. Amoebiasis: incidence at Royal North Shore Hospital, Sydney. Med J Aust 1977 Janl-8;l(l-2):ll-3).
The limited side effects of metronidazole are generally tolerable, transient, or reversible. (Stranz MH, Bradley WE. Metronidazole (Flagyl IV, Searle). Drug Intell Clin Pharm 1981 Nov;15(ll):838-46.)
4

Intestinal amoebic infections are caused by trophozoites, which attach to the colonic mucosa and cause lesions of colon, cecum and rectum. (Reed SL. Amoebiasis and infection with free living amoebas in Fauci et al eds 'Harrison's Principles of internal medicine', 14th edition, McGraw Hill: New York, Vol2, 1998: 1178-80). Anti-amoebic that can be specifically delivered to the colon could therefore reduce the side effects and improve pharmacological response at smaller doses. Conventional dosage forms are ineffective for delivering drugs to the colon due to absorption and/or degradation of the active ingredient in the upper part of the GI tract (Reddy SM, Sinha VR, Reddy SR. Novel oral colon-specific drug delivery systems for pharmacotherapy of peptide and nonpeptide drugs. Drugs of today. 1995; 35: 537-80). Metronidazole diffuses well into all tissues but has only a relatively minor impact on the colonic flora (Finegold SM. Metronidazole. Ann Intern Med 1980 Oct;93(4):585-7). Modification of oral formulation of metronidazole by using polymers that can deliver the drug directly to the colon would increase its concentration in the local tissue and thereby its efficacy. Modification of the formulation to release some part of the drug in the duodenum would also prove useful in combating infections like giardiasis by providing local action. In the prior art various drug delivery systems preferably oral tablets have been suggested for treatment of parasitoses and infection of the gastrointestinal tract. The US Patent no. 5,549,911 provides galenic form of 5-nitro imidazole derivates, which are effective in treatment of parasitoses and infections of the entire gastro intestinal tract. It relates to the said derivates comprising a combination of micro granules of 5 -nitro imidazole derivatives consisting, on one hand, of gastro resistant micro granules and on the other hand of prolonged release micro granules, the pharmaceutical composition comprising such derivates and the micro granules as inter
5

immediate in the preparation of the galenic form. Typically the galenic form provided the said product comprises the natural granular carrier coated with active layer of 5-nitro imidazole derivates and a binding agent, a gastro resistant external layer comprising excipient ensuring the registrants of the coating the pH value 4.5 - 5.5. The said invention provides the drug delivery system viz., comprising of the active ingredient in the form of coated granules. This drug delivery system has a disadvantage in the sense that both the granules would be released immediately. The coating of the granule -I would dissolve at pH > 5.5 i.e. only at the entrance of small intestine and the drug would be released
Another US patent no. 6,039,975 [Shah, et al.] Provides a tablet system of drug administration, which comprises an outer enteric coating, and inner semi preamble polymer membrane containing a plasticizer and a central core comprises swelling excipients and an active ingredient. This drug system releases the drug consistently in the colon by the time dependent explosion mechanism, which is useful and suitable for delivery in the colon only. The drug delivery system provided by the said combines a time dependent explosion approach and enteric coating to achieve precise and predictable delivery of drug only to the colon. This is achieved by combination of an acid resistant semi-permeable membrane of a polymer containing a plasticizer and a swellable core, which will cause the membrane to burst consistently after 4-6 hours exposure to small intestinal fluid.
The above two patents teach the available drug delivery system NDDS having certain advantages and which are dependent upon certain parameters like pH or swelling plasticizer for on said drug delivery. The drug delivery systems provided by these patents have following drawbacks. 1. Irregular and erratic drug release is possible.
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2. Needs skilful operations and specific machine required
3. Dose dumping is possible.
To overcome the specificity of the earlier systems an integrated approach for drug delivery system useful for colon specific delivery and the delivery to other sites is provided by the present invention. The drug delivery system designated as CDDS contains the active ingredient in suitable orally administrable devices or means like modified tablets consisting of at least two layers, which can be referred to as CDDS containing the drug formulation manipulated by the use of polymers that are degraded in the intestinal mucosa, thereby releasing the drug specifically at its site of action. The said drug delivery system generically described as CDDS, comprises the active ingredient divided into two separate zones, one embedded in another, and each forming an independent tablet separated by the release mechanism is unique one and control the drug doses required by the patient for the particular span of time. The CDDS drug delivery system is described herein with using Metronidazole as representative active ingredient, however the application of the present invention is not limited to the said active ingredient. Metronidazole in particular has a shelf life of 9 hours and hence the proposed CDDS drug delivery system consists of a device, which will administer two doses such that the second instalment of the drug would be released in the colon after 8- .10 hours of oral ingestion.
The main object of the present invention therefore is to provide an improved drug delivery system designated as CDDS.
Another objective is to provide the drug delivery system capable of delivering the active ingredient at desired specific intervals depending upon the active ingredient.
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Yet another objective is to provide a drug delivery system capable of delivering the
drug such as Metronidazole, Tinidazole to specific sites such as colon and nearby
organs.
Conventional dosage forms for administration of amoebicides are ineffective for
delivering drugs to the colon due to absorption and/or degradation of the active
ingredient in the upper part of the Gastro intestinal tract. Metronidazole diffuses well
into all tissues but has only a relatively minor impact on the colonic flora.
Modification of oral formulation of metronidazole by using polymers that can deliver
the drug directly to the colon would increase its concentration in the local tissue and
thereby its efficacy. Modification of the formulation to release some part of the drug
in the duodenum would also prove useful in combating infections like giardiasis by
providing local action. Metronidazole site-specific delivery system provided by the
present invention, releases some amount of drug directly in the duodenum where local
action of the drug takes place. This ensures that a high concentration of the drug is
achieved with faster action. The remaining amount of the drug is released in the
colon in a sustained release fashion for its local action in the colon. Hence the
frequency of dosage can be reduced with this novel formulation ensuring a better
tolerability profile.
The present invention provides CDDS system, which shows the drug release profile
as follows:
The tablet contains 400 mg of metronidazole
There is a silent phase of 2 hours immediately after administration, during which no
drug is released, first dose of 200 mg of drug is released after 2 hours of oral intake.
8

Further, there is silent period of 2 hours, during which almost negligible amount will be released. The remaining 200-mg of drug will be released in the colon, in a sustained released fashion over a period of 4 hours.
Following oral administration metronidazole is well absorbed. The pharmacokinetic profile of Metronidazole formulated as a colon specific drug delivery system differs from that of the conventional preparations. The Pharmacokinetic profile of this colon specific drug delivery follows a biphasic response with 2 peaks appearing at a gap of approximately 3.5 hours. The first peak plasma concentration is 2.42-mcg/ ml and appears at 4.78 hours, the second peak plasma concentration is 5.01 mcg/ml achieved at 8.28 hours. These two peaks observed, correspond to the drug released at different time intervals.
Conventional Metronidazole after single dose shows peak plasma concentrations between 2-2.5 hours with dose dependent change in C max values, e.g. it is 12 mcg/ml for 500mg. The levels decline as time goes by. But in Metronidazole CDDS, at around 2 hours after administration 0.195-mcg/ml plasma level of drug is achieved initially. After the release in duodenum the peak plasma levels are reached at 4.78 hours .The plasma levels drop and then again they slowly rise till a peak is achieved at around 5-5.5 hours. The plasma levels steadily rise coinciding with sustained release of the drug in the colon. At around 9.5 hours peak plasma concentrations of 2.835 mcg/ml are achieved which lasts with just a slight drop till 12 hours. Therefore, optimally, the drug lasts for 7-8 hours in the colon where its action is most needed in amoebiasis and giardiasis.
As opposed, in conventional tabs, the levels decline steadily after 5-6 hours of oral administration leaving very little drug to act in colon. The comparison is given in table-1 hereinbelow.
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A Double-Blind, Randomized, Comparative trials of Colon Targeted Metronidazole versus conventional oral metronidazole tablets in the treatment of intestinal amoebiasis was conducted. The trials were conducted at three centres. Each centre evaluated 80 patients, with 40 patients in each group, which gave us a pooled data of 240 evaluable patients. 40 patients in each centre received Metronidazole CDDS 400mg twice daily; while the remaining 40 received Metronidazole conventional tablets 400 mg thrice daily for a period of 5 days.
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It was observed that:
• The efficacy of Metronidazole CDDS (400 mg twice daily) was found to be comparable to that of Metronidazole conventional tablet (400 mg thrice daily)
• The incidence of nausea was lower in the Metronidazole CDDS group. The number of patients who reported nausea went up from a base line value of 10% to 27.5% (day 3) and 18.75 % (day 6) in patients in the Metronidazole conventional group. Whereas in the Metronidazole CDDS group the incidence reduced from a base line value of 12.5 % to 7.5% (day 3) and 5% (day 6). This is seen to be of statistical significance (p<0.0023).
• No incidences of vomiting were seen with the Metronidazole CDDS group whereas, in the Metronidazole conventional1 group, 5% patients reported vomiting on day 3 and 3.75% on day 6.
• Only 1.25% patients in the Metronidazole CDDS reported metallic taste at the end of the study on day 6, whereas in the conventional Metronidazole group, 7.5% patients each reported metallic taste on day 3 and day 6.
From the above it could be observed that Metronidazole CDDS given twice daily was found to be better tolerated with comparable efficacy to that of conventional metronidazole tablets given thrice daily in the treatment of intestinal amoebiasis. The figure in the drawing [schematic diagram not to the scale] accompanying this specification describes the cross section of a CDDS as provided by the present invention. The said CDDS comprises a core (1), the outer coat (2), the seal coat (3) and enteric coat (4). Each core, the outer coat, the enteric coat and the seal coat comprises of ingredients mentioned hereinbelow.
Accordingly the present invention provides an improved colon drug delivery system generically described as CDDS which comprises,
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a) A core comprising of active ingredient, a filler a matrix forming agent excipient, a binder, a lubricant and glidants
b) An Outer coat, embedding the core, comprising 50 to 500 mg. of active ingredient, a filler excipient, a binder, a disintegrant, a lubricant and glidants,
c) The said outer coat covered by a seal coat, the seal coat coated by a gastric resistant enteric coat
In one of the embodiments of the present invention the composition of the core layer of each tablet may be as shown in Table -2.
Table -2: Composition of outer coat

Such that 1 + 2 + 3 + 4 < 100%
In yet another embodiment the composition of the outer coat of each tablet may be as
shown in Table-3.
Table-3: Composition of core

Such that 1 + 2 + 3 + 4 + 5 < 100%
In another embodiment the active ingredient in the core and the outer coat may be
antiprotozoal drugs such as Metronidazole, Tinidazole.
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In another embodiment the filler excipient in the core and outer coat may be Lactose
Microcrystalline Cellulose, Starch and Dicalcium phosphate
In yet another embodiment the binder in the core and the outer coat may be Polyvinyl
Pyrrolidone, Starch and Gelatine.
In still another embodiment the lubricant in the core and the outer coat may be
Magnesium stearate, Calcium Stearate, Talc and Starch.
In another embodiment the glidant in core and outer coat may be Talc or Colloidal
Silicon Dioxide or mixture thereof.
In yet another embodiment the disintergrant in the core may be Sodium Starch
glycollate, Crospovidone, Croscarmellose and Dried Starch.
In still another embodiment the swellable polymer separating the outer coat, the core
and the seal coat may be Carbopol, Gum Acacia, Xanthan Gum, Hydroxy Propyl
Methyl Cellulose (HPMC) of K-4M or K-100M grade.
Still another embodiment the enteric coat may be of Poly Vinyl Acetate Phthalate
(PVAP), Cellulose Acetate Phthalate (CAP), Methacrylic acid copolymer or Ethyl
Cellulose soluble at pH 5.5 and above
The present invention also provides a process for the preparation of CDDS, which
comprises separately preparing two granule mixes for core and coat tablets as per the
compositions mentioned herein above, loading the mixes to the hoppers of the
compression coating machine capable of preparing the tablet in tablet to obtain the
CDDS and effecting the seal coat and enteric coat on the said tablet by conventional
coating procedures.
The new drug delivery system provided by the present invention and a process for the
preparation thereof is described hereinbelow with examples, which are illustrative
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only and should not be construed to limit the scope of the present invention in any manner whatsoever.
EXAMPLE-1 This example shows the preparation of CDDS using Carbopol 934 [p] grade. The mixtures for the coat and the core layer were prepared as per the composition per tablet as mentioned below in Table No. 4

Preparation of the mixture for outer Coat:
Metronidazole was crushed and sifted through 80 mesh, Lactose & Microcrystalline Cellulose were sifted through 40 mesh and mixed was sifted through 40 mesh and mixed thoroughly to obtain a uniform blend. The Povidone [PVP K-30] was dissolved in a mixture of Isopropyl Alcohol and water in the ratio of 1:1 and the solution was filtered through 100 mesh. The uniform blend was then granulated with the PVP K-30 solution and dried at 50°C. The dried mixture was lubricated with a mixture of Colloidal Silicon Dioxide, Magnesium Stearate and CrosPovidone, which were previously sifted through 40 mesh. Preparation of mixture for Core:
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Metronidazole was crushed and sifted through 80 mesh and Methocel K-100 M and Lactose through 40 mesh and mixed thoroughly to obtain a homogenous blend. Povidone [PVP K-30] was dissolved in a mixture of Isopropyl Alcohol and water in the ratio of 1:1. The homogenous blend was granulated using this mixture and dried at 50CC. The granules were lubricated with a mixture of Magnesium Stearate and Xanthan gum, Carbopol 934 [p], which was pre-sifted through 40 mesh. Both core and coat granules were loaded on compression machine in two separate hoppers. The core granules were compressed lightly and transferred mechanically in the coat granules cavity. The coat granules were fed mechanically in the same cavity and compression was done to form a tablet in tablet.
PROCEDURE FOR SEAL AND ENTERIC COATING SEAL COAT
In Isopropyl Alcohol Hydroxypropyl Methyl Cellulose (15 cps) 5% dispersed under mechanical stirring, followed by addition of Methylene chloride 45%, Isopropyl alcohol 50% . The mixture was stirred for 40 minutes to get homogeneous viscous slurry. The slurry was filtered through 200 # nylon cloth and this solution was used for seal coating.
ENTERIC COAT
Opadry -OY-P-7171 colourcon (5%) and Lake of quinoline yellow (0.02%) was
dispersed in Isopropyl alcohol under stirring. To this Methylene chloride was added and the mixture was homogenized for 30 minutes under stirring and the homogenized mixture was filtered through 200 mesh nylon cloth.
Tablets were loaded in a coating pan. The pan was rotated at 6-8 rpm and seal coat solution was sprayed under continuos drying followed by applying enteric coat to form a homogenous, acid-resistant film.
15

The release pattern of these tablets prepared as above was tested in different media and the results are given in table -5
Table-5

EXAMPLE-2 This example shows the preparation of CDDS using Carbopol 980 grade. The mixtures for the coat and the core layer were prepared as per the composition per tablet as mentioned below in Table -6
Table-6


Preparation of the mixture for outer Coat:

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Metronidazole was crushed & sifted through 80 mesh, Lactose & Microcrystalline
Cellulose were sifted through 40 mesh and mixed was sifted through 40 mesh and
mixed thoroughly to obtain a uniform blend. The Povidone [PVP K-30] was
dissolved in a mixture of Isopropyl alcohol and water in the ratio of 1:1 and the
solution was filtered through 100 mesh. The uniform blend was then granulated with
the POVIDONE [PVP K-30] solution and dried at 50 °C. The dried mixture was
lubricated with a mixture of Colloidal Silicon Dioxide, Magnesium Stearate and
CrosPovidone, which were previously sifted through 40 mesh.
Preparation of mixture for Core:
Metronidazole was crushed and Methocel K-100 M and Lactose sifted through 40
mesh and mixed thoroughly to obtain a homogenous blend. Povidone [PVP K-30]
was dissolved in a mixture of Isopropyl Alcohol and water in the ratio of 1:1. The
homogenous blend was granulated using this mixture and dried at 50°C. The granules
were lubricated with a mixture of Magnesium Stearate and Carbopol 980, which was
pre-sifted through 40 mesh.
Both core and coat granules were loaded on compression machine in two separate
hoppers. The core granules were compressed lightly and transferred mechanically in
the coat granules cavity. The coat granules were fed mechanically in the same cavity
and compression was done to form a tablet in tablet.
PROCEDURE FOR SEAL AND ENTERIC COATING SEAL COAT
In Isopropyl Alcohol Hydroxypropyl Methyl Cellulose (15 cps) 5% dispersed under mechanical stirring, followed by addition of Methylene chloride 45%, Isopropyl alcohol 50% . The mixture was stirred for 40 minutes to get homogeneous viscous slurry. The slurry was filtered through 200 # nylon cloth and this solution was used for seal coating.
17

ENTERIC COAT
Opadry -OY-P-7171 colourcon (5%) and Lake of quinoline yellow (0.02%) was
dispersed in Isopropyl alcohol under stirring. To this Methylene chloride was added
and the mixture was homogenized for 30 minutes under stirring and the homogenized
mixture was filtered through 200 mesh nylon cloth.
Tablets were loaded in a coating pan. The pan was rotated at 6-8 rpm and seal coat
solution was sprayed under continuous drying followed by applying enteric coat to
form a homogenous, acid-resistant film.
The release pattern of these tablets prepared as above was tested in different media
and the results are given in Table-7
Tabte-7

EXAMPLE-3 This example shows the preparation of CDDS using Polycarbophil & Xanthan gum. The mixtures for the coat and the core layer were prepared as per the composition per tablet as mentioned below in table-8
18


Preparation of the mixture for outer Coat
Metronidazole was crushed & sifted through 80 mesh Lactose & starch were sifted through 40 mesh and mixed was sifted through 40 mesh and mixed thoroughly to obtain a uniform blend. The Povidone [PVP K-30] was dissolved in a mixture of Isopropyl Alcohol and water in the ratio of 1:1 and the solution was filtered through 100 mesh. The uniform blend was then granulated with the Povidone [PVP K-30] solution and dried at 50°C. The dried mixture was lubricated with a mixture of Colloidal Silicon Dioxide, Magnesium Stearate and Crospovidone along with Macrocrystalline cellulose, which were previously sifted through 40 mesh. Preparation of mixture for Core:
Metronidazole was crushed and sifted through 80 mesh and Methocel K-100 M and Lactose through 40 mesh and mixed "thoroughly to obtain a homogenous blend. Povidone [PVP K-30] was dissolved in a mixture of Isopropyl alcohol and water in the ratio of 1:1. The homogenous blend was granulated using this mixture and dried
19

at 50°C. The granules were lubricated with a mixture of Magnesium Stearate and Xanthan gum & polycarbophil, which was pre-sifted through 40 mesh. Both core and coat granules were loaded on compression machine in two separate hoppers. The core granules were compressed lightly and transferred mechanically in the coat granules cavity. The coat granules were fed mechanically in the same cavity and compression was done to form a tablet in tablet.
PROCEDURE FOR SEAL AND ENTERIC COATING SEAL COAT
In Isopropyl Alcohol Hydroxypropyl Methyl Cellulose (15 cps) 5% dispersed under mechanical stirring, followed by addition of Methylene chloride 45%, Isopropyl alcohol 50% . The mixture was stirred for 40 minutes to get homogeneous viscous slurry. The slurry was filtered through 200 # nylon cloth and this solution was used for seal coating.
ENTERIC COAT
Opadry -OY-P-717I colourcon (5%) and Lake of quinoline yellow (0.02%) was
dispersed in Isopropyl alcohol under stirring. To this Methylene chloride was added
and the mixture was homogenized for 30 minutes under stirring and the homogenized
mixture was filtered through 200 mesh nylon cloth.
Tablets were loaded in a coating pan. The pan was rotated at 6-8 rpm and seal coat
solution was sprayed under continuous drying followed by applying enteric coat to
form a homogenous, acid-resistant film.
The release pattern of these tablets prepared as above was tested in different media
and the results are given table-9
20

This example shows the preparation of CDDS using Methocel K-4M grade along with polycarbophil & Carbopol 980.
The mixtures for the coat and the core layer were prepared as per the composition per tablet as mentioned below in table-10
Table-10

Preparation of the mixture for outer Coat:
Metronidazole was crushed and sifted through 80 mesh, Lactose & starch were sifted
through 40 mesh and mixed was sifted through 40 mesh and mixed thoroughly to
21

obtain a uniform blend. The Povidone [PVP K-30] was dissolved in a mixture of
Isopropyl Alcohol and water in the ratio of 1:1 and the solution was filtered through
100 mesh. The uniform blend was then granulated with the Povidone [PVP K-30]
solution and dried at 50 °C. The dried mixture was lubricated with a mixture of
Colloidal Silicon Dioxide, Magnesium Stearate and Crospovidone, which were
previously sifted through 40 mesh.
Preparation of mixture for Core:
Metronidazole was crushed and sifted through 80 mesh and Methocel K-100 M and
Lactose through 40 mesh and mixed thoroughly to obtain a homogenous blend.
Povidone [PVP K-30] was dissolved in a mixture of Isopropyl Alcohol and water in
the ratio of 1:1. The homogenous blend was granulated using this mixture and dried at
50°C. The granules were lubricated with a mixture of Magnesium Stearate and
carbopol 980 , polycarbophil, which was pre-sifted through 40 mesh.
Both core and coat granules were loaded on compression machine in two separate
hoppers. The core granules were compressed lightly and transferred mechanically in
the coat granules cavity. The coat granules were fed mechanically in the same cavity
and compression was done to form a tablet in tablet.
PROCEDURE FOR SEAL AND ENTERIC COATING SEAL COAT
In Isopropyl Alcohol Hydroxypropyl Methyl Cellulose (15 cps) 5% dispersed under
mechanical stirring, followed by addition of Methylene chloride 45%, Isopropyl
alcohol 50% . The mixture was stirred for 40 minutes to get homogeneous viscous
slurry. The slurry was filtered through 200 # nylon cloth and this solution was used
for seal coating.
22

ENTERIC COAT
Opadry -OY-P-7171 colourcon (5%) and Lake of quinoline yellow (0.02%) was dispersed in Isopropyl alcohol under stirring. To this Methylene chloride was added and the mixture was homogenized for 30 minutes under stirring and the homogenized mixture was filtered through 200 mesh nylon cloth. Tablets were loaded in a coating pan. The pan was rotated at 6-8 rpm and seal coat
solution was sprayed under continuos drying followed by applying enteric coat to
form a homogenous, acid-resistant film.
The release pattern of these tablets prepared as above was tested in different media
and the results are given in table-11

EXAMPLE-5 This example shows the preparation of CDDS using Polycarbophil grade. The mixtures for the coat and the core layer were prepared as per the composition per tablet as mentioned below in table-12


Preparation of the mixture for outer Coat:
Metronidazole was crushed & sifted through 80 mesh, Lactose & starch were sifted through 80 mesh and mixed was sifted through 40 mesh and mixed thoroughly to obtain a uniform blend. The Povidone [PVP K-30] was dissolved in a mixture of Isopropyl alcohol and water in the ratio of 1:1 and the solution was filtered through 100 mesh. The uniform blend was then granulated with the Povidone [PVP K-30] solution & dried at 50°C. The dried mixture was lubricated with a mixture of Colloidal Silicon Dioxide, Magnesium Stearate and Crospovidone along with microcrystalline cellulose, which were previously sifted through 40 mesh. Preparation of mixture for Core:
Metronidazole was crushed and sifted through 80 mesh and Methocel K-100 M and Lactose through 40 mesh and mixed thoroughly to obtain a homogenous blend. Colour lake of quinoline yellow was sifted through 100 mesh and mixed uniformly with above blend Colour Lake of quinoline yellow was sifted through 100 mesh and mixed uniformly with above blend. Povidone [PVP K-30] was dissolved in a mixture
24

of Isopropyl Alcohol and water in the ratio of 1:1. The homogenous blend was
granulated using this mixture and dried at 50°C. The granules were lubricated with a
mixture of Magnesium Stearate and polycarbophil, which was pre-sifted through 40
mesh.
Both core and coat granules- were loaded on compression machine in two separate
hoppers. The core granules were compressed lightly and transferred mechanically in
the coat granules cavity. The coat granules were fed mechanically in the same cavity
and compression was done to form a tablet in tablet.
PROCEDURE FOR SEAL AND ENTERIC COATING SEAL COAT
In Isopropyl Alcohol Hydroxypropyl Methyl Cellulose (15 cps) 5% dispersed under
mechanical stirring, followed by addition of Methylene chloride 45%, Isopropyl
alcohol 50% . The mixture was stirred for 40 minutes to get homogeneous viscous
slurry. The slurry was filtered through 200 # nylon cloth and this solution was used
for seal coating.
ENTERIC COAT
Opadry -OY-P-7171 colourcon (5%) and Lake of quinoline yellow (0.02%) was
dispersed in Isopropyl alcohol under stirring. To this Methylene chloride was added
and the mixture was homogenized for 30 minutes under stirring and the homogenized
mixture was filtered through 200 mesh nylon cloth.
Tablets were loaded in a coating pan. The pan was rotated at 6-8 rpm and seal coat
solution was sprayed under continuos drying followed by applying enteric coat to
form a homogenous, acid-resistant film.
The release pattern of these tablets prepared as above was tested in different media
and the results are tabulated in table-13
25


This example shows the preparation of CDDS using Polycarbophil grade. The mixtures for the coat and the core layer were prepared as per the composition per tablet as mentioned below in table-14

Preparation of the mixture for outer Coat:
Tinidazole was crushed & sifted through 80 mesh, Lactose & starch were sifted through 80 mesh and mixed was sifted through 40 mesh and mixed thoroughly to obtain a uniform blend. The Povidone [PVP K-30] was dissolved in a mixture of
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Isopropyl alcohol and water in the ratio of 1:1 and the solution was filtered through 100 mesh. The uniform blend was then granulated with the Povidone [PVP K-30] solution & dried at 50°C. The dried mixture was lubricated with a mixture of Colloidal Silicon Dioxide, Magnesium Stearate and Crospovidone along with microcrystalline cellulose, which were previously sifted through 40 mesh. Preparation of mixture for Core:
Tinidazole was crushed and sifted through 80 mesh and Methocel K-100 M and Lactose through 40 mesh and mixed thoroughly to obtain a homogenous blend. Colour lake of quinoline yellow was sifted through 100 mesh and mixed uniformly with above blend Colour Lake of quinoline yellow was sifted through 100 mesh and mixed umTormry with" above bknd. Povidone [PVP K-30] was dissolved in a mixture of Isopropyl Alcohol and water in the ratio of 1:1. The homogenous blend was granulated using this mixture and dried at 50°C. The granules were lubricated with a mixture of Magnesium Stearate and polycarbophil, which was pre-sifted through 40 mesh.
Both core and coat granules were loaded on compression machine in two separate hoppers. The core granules were compressed lightly and transferred mechanically in the coat granules cavity. The coat granules were fed mechanically in the same cavity and compression was done to form a tablet in tablet.
PROCEDURE FOR SEAL AND ENTERIC COATING SEAL COAT
In Isopropyl Alcohol Hydroxypropyl Methyl Cellulose (15 cps) 5% dispersed under mechanical stirring, followed by addition of Methylene chloride 45%, Isopropyl alcohol 50% . The mixture was stirred for 40 minutes to get homogeneous viscous slurry. The slurry was filtered through 200 # nylon, cloth and this solution was used for seal coating.
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ENTERIC COAT
Opadry -OY-P-7171 colourcon (5%) and Lake of quinoline yellow (0.02%) was
dispersed in Isopropyl alcohol under stirring. To.this Methylene chloride was added
and the mixture was homogenized for 30 minutes under stirring and the homogenized
mixture was filtered through 200 mesh nylon cloth.
Tablets were loaded in a coating pan. The pan was rotated at 6-8 rpm and seal coat
solution was sprayed under continuos drying followed by applying enteric coat to
form a homogenous, acid-resistant film.
The release pattern of these tablets prepared as above was tested in different media
and the results are tabulated in table-15.

The Advantages of the CDDS drug delivery system of the present invention are as follows:
• The CDDS provides local action in the duodenum and colon where the trophozites of amoeba and giardia reside.
• Since the drug remains for a long period of time at high levels in the plasma, it takes care of extra intestinal amoebiasis.
• It affords local action in duodenum e.g. in giardiasis and in colon for amoebiasis.
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• Conventional 400 mg metronidazole tablets are absorbed into systemic circulation completely from duodenum. CDDS i.e. the Metronidazole site-specific drug delivery system releases only 200 mg of metronidazole in the duodenum, which is absorbed systemically. The remaining 200 mg of metronidazole from the metronidazole colon specific drug delivery system is released in the colon in a sustained release fashion. Thus a high local concentration of the drug is achieved in the colon, which is helpful in the treatment of intestinal amoebiasis.
• Clinical trials have proven that CDDS administered twice daily has a comparable efficacy and better tolerability profile as compared to the conventional metronidazole preparations which are administered thrice daily.
• Limited clinical trials have proven that unlike the conventional Metronidazole tablets, the colon specific CDDS Metronidazole tablets has lower incidences of side effects such as nausea, vomiting and metallic taste. The better side effect profile is due to the release of the drug at the site of action.
• CDDS affords lesser frequency of dosage- Twice daily dosage compared to thrice daily for
conventional tablets.
Excellent patient Compliance due to twice daily dosing as compared to thrice daily
dosing of metronidazole conventional tablets
• Better tolerability due to lesser side effects
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We Claim:
1. An improved site specific drug delivery system generically described as Colon Drug
Delivery System (CDDS), which comprises,
a) a core comprising active ingredient, a filler excipient, a matrix forming
agent excipient, a binder, a lubricant and glidants
b) an Outer coat embedding the core comprising active ingredient, a filler
excipient, a binder, a disintegrant, a lubricant and glidants,
c) the said outer coat covered by a seal coat, the seal coat coated by a gastric
resistant enteric coat.
2. An improved colon drug delivery system as claimed in claim 1, wherein the composition of the core layer of each tablet is as shown in Figl.
3. An improved colon drug delivery system as claimed in claim 1, wherein the active ingredient in the core and the outer coat is selected from a group of antimicrobial agents consisting of Metronidazole and Tinidazole.
4. An improved colon drug delivery system as claimed in claim 1, wherein the filler excipient in the core and outer coat is at least one filler excipient selected from a group of filler excipients consisting of Lactose Microcrystalline Cellulose, Starch, and Dicalcium
phosphate.
5. An improved colon drug delivery system as claimed in claim 1, wherein the binder is at least one binder selected from a group of binders consisting of Polyvinyl Pyrrolidone, Starch, and Gelatine.
6. An improved colon drug delivery system as claimed in claim 1, wherein the lubricant is at least one lubricant selected from a group of lubricants consisting of Magnesium stearate,
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Calcium Stearate, Talc and Starch..
7. An improved colon drug delivery system as claimed in claim 1, wherein the glidant is at least one glidant selected from a group of glidants consisting of Talc and Colloidal Silicon Dioxide.
8. An improved colon drug delivery system as claimed in claim 1, wherein the disintergrant in the core coat is at least one disintegrant selected from a group of disintegrant consisting of Sodium Starch glycollate, Crosspovidone, Crosscarmellose, and Dired Starch.
9. An improved colon drug delivery system as claimed in claim 1, wherein the core coat is separated from the outer coat by a swellable polymer selected from a group of swellable polymers consisting of Carbopol, Gum Acacia, Xanthan Gum, HPMC K-4M and HPMC K-100M.
10. An improved colon drug delivery system as claimed in claim 1, wherein the
composition of the core layer of each tablet is such that the proportions of the active ingredient,
fillers, binders, and lubricants in the composition are in the ranges of 20 - 70 %, 20 - 70 %,
5-15%, 5-15% respectively(as shown in Table 16) such that sum total
of the proportions in percentages is below 100.
11. An improved colon drug delivery system as claimed in claim 1, wherein the composition
of the outer coat of each tablet is such that the proportions of the active ingredient, gel/matrix
forming agent fillers, binders, and lubricants in the composition are in the ranges of 20 - 70
%, 5-50%, 10-50%, 5-15%, 5-15% respectively(as shown in Table 17)
such that sum total of the proportions in percentages is below 100.
12. An improved colon drug delivery system as claimed in claim 1, wherein the outer gastric
resistant coat comprises at least one polymer selected from a group of polymers consisting
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of PVAP, CAP, Methacrylic acid copolymer and Ethyl Cellulose.
13. A process for preparation of Colon Drug Delivery System (CDDS) which comprises separately preparing two granule mixes for core and coat tablets, loading said granule mixes to the hoppers of the compression coating machine capable of preparing a tablet in tablet to obtain Colon Drug Delivery System (CDDS).
14. An improved colon drug delivery system as fully described hereinbefore with reference to examples 1 to 6 therein.

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