FORM 2


THE PATENTS ACT, 1970
(39 OF 1910)

COMPLETE SPECIFICATION
(See section 10)
CONTROLLED RELEASE COATED TABLET HAVING PROLONGED GASTRIC RETENTON
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA.
ANDHERI-KURLA ROAD, ANDHERI(E), MUMB AI-400059. MAHARASHTRA, INDIA.
The following specification particularly describes and ascertains the nature of this invention
and the manner in which it is to be performed.

The present invention relates to controlled release coated tablets that are retained for longer
period in the stomach.
BACKGROUND OF THE INVENTION
The art is replete with many references relating to drug delivery systems that when orally
administered are retained in the stomach. Several such systems disclosed in prior art relate to
retention of system in the stomach because the size of the system is large and thereby gastric
emptying is delayed.
Prior art systems that provide a control on the release of the drug and also are retained in stomach
because of their size and shape include certain drawbacks. The major drawback of a large
majority of the disclosed prior art systems that have become commercially useful is that they are
not sufficiently large in size initially but attain their size by swelling to several times their initial
size this entails a risk that the system would be emptied from the stomach before it swells. This
drawback has been overcome to an extent by systems that swell rapidly, however such systems
must include enough quantities of swelling agents that swell rapidly but despite the internal
swelling pressure created must not disintegrate earlier than desired. These requirements make the
formulator's task difficult. There may be further limitations in formulation options for the
formula tor because the drug containing matrix should release drug at a desired controlled release
rale while also retaining its size. For example, this may be difficult when the dose of the active
ingredient is large and relatively smaller quantities of pharmaceutical excipients suffice to
provide the controlled release, A matrix so formed containing higher proportions of active
ingredients as compared to other pharmaceutical excipients often erodes or disintegrates into parts
earlier than desired for gastric retention. For example, systems disclosed in, United States Patent
Number 4.777,033 (Patent '033) were found to have a drawback in that-it did not remain intact
when subjected to agitation in an aqueous medium. On the other hand systems that are designed
to avoid erosion or disintegration may be eliminated in the stools in an intact form which raises
an apprehensions in the patient about the quality of the tablets or that he did not absorb the active
ingredient.
There remains a need for a drug delivery system that provides an independent controlling
mechanism for providing a slow delivery of the active ingredient and an independent controlling
2

mechanism for providing size and rigidity and retaining size so as to be retained in the stomach
over the desired period of release and which system is completely eroded or disintegrated in the
intestine.
We described a novel drug delivery system in WO 2005/039481 (herein after referred to as '481
publication) the same is incorporated herein by reference. This patent application describes a
novel oral drug delivery system that comprises a core with drug composition and a coating
surrounding said core. In one embodiment, the coated tablet was designed to include a design
feature comprising a swellable composition adjacent to a preselected surface of the coating. On
imbibing water, the swellable composition swells and exerts pressure on the coating, particularly
at the preselected surface, and the coating from only that preselected surface is removed. At the
same time, the coating maintains its physical form and rigidity on other surfaces of the system to
form a cup-shaped platform. The system was designed such that coating from one or more of the
preselected surfaces was removed, and drug release occurred from the exposed surface. The
exposed surface area remains constant over the periods of release and the drug was released at a
uniform or zero-order rate from the system.
However, we have found that the oral drug delivery system of 481 can be modified to provide
systems of the present invention in the form of coated tablets that are suitable for gastric retention
and overcome the aforesaid drawbacks of the prior art gastric retention systems. The coated
tablets of the present invention have an initial size and rigidity that is retained at least along one
dimensions of the tablets and along at least one more dimension the size and rigidity is retained
partially when the tablets are subjected to agitation in an aqueous medium. In other words, at least
along one dimension the original size is retained and along a second dimension the size decreases
as the components of the coated tablets erode or dissolve until an intermediate size is achieved
and thereafter the coated tablets do not substantially erode or dissolve in the gastric fluids. The
intermediated size tablet remnant can be emptied from the stomach without gastric obstruction,
and in the intestine it can disintegrate or erode or dissolve.
3

SUMMARY OF THE INVENTION
The present invention provides a coated tablet having prolonged gastric retention comprising
A. a core comprising two or more compositions in the form of compressed layers wherein at
least one composition comprises a therapeuticaily active ingredient and rate controlling
excipienls
B. a coat rupturing system comprising
1. one of aforesaid composition in the form of a swellable compressed layer
comprising a swelling excipient
2. a coating comprising a film former adjoining said swellable compressed layer
and surrounding said core,
wherein the coating ruptures from at least one of the surfaces when the coated tablet is in an
aqueous environment
C. a second inert compressed layer comprising an inert excipient, which is insoluble in gastric
fluids but soluble in at least one region of the intestine, wherein the inert excipient is present
in amounts such that the inert compressed layer retains its size at least until coated tablet is
emptied from the stomach.
DESCRIPTION OF THE DRAWINGS
Many aspects of the invention can be better understood with reference to the following figures.
The figures only represent one of the embodiments of the present invention. The embodiments
are meant only for the purpose of illustration of the present invention. The components in the
drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the
principles of the present invention.
Different parts of one of the embodiments of coated tablet of the present invention are given in
Figure land are labeled and the labeling is described herein below
1. passageway
2. Swellable compressed layer
3. Composition in the form of compressed layer comprising therapeuticaily active ingredient
4. second inert compressed layer
5. Coating having a coat rupturing system
6. Aqueous environment, arrow marks depicting permeation of water through the passageway
4

(a) external surface of the inert compressed layer
(b) internal surface of the inert compressed layer
The term ' external surface' of the inert compressed layer herein means surfaces that are
separated from the environment only by the costing and do not adjoin any other composition and
the term 'internal surface' herein means the surface that adjoins another composition.
Figure 1 represents one embodiment of the present invention wherein coated tablet is in the form
of a trilayer. The three layers are planar layers.
These layers are described as follows:
A sweliable compressed layer (2), active ingredient composition layer (3) and second inert
compressed layer (4). The external surface (a) and an internal surface (b) of the inert compressed
layer are shown.
The trilayer tablet core is coated with a coating (5). The coating is a defective or a reactive
coating as described in our co-pending application W02005/039481. The coating together with a
swellable layer forms a coat rupturing system. It also forms a cup to hold the inert compressed
layer. Together they form a reliable means of retaining rigidity and size along one dimension.
In the embodiment of the present invention described by figures, the coat rupturing system
comprises a laser-drilled passageway on the coating and a swellable compressed layer. The
passageway is created on the surface of the coating in the immediate vicinity of the swellable
compressed layer. Upon contact of coating with water enters through the passageway and the
swellable compressed layer swells. It exerts pressure on the coating surface having a passageway
and ihe coating ruptures from that surface only while remaining intact on other surfaces. Thus,
upon contact with aqueous environment, the coating gets ruptured leaving the coated tablet in the
form of a cup from which the active ingredient is released. Figure 2 and Figure 3 represent
different stages of the mechanism by which the active ingredient is released in a desired manner.
5

Figure 2 represents the stage where the coated tablet comes in contact with the aqueous
environment. Upon contact with the aqueous environment (6), there is a rapid ingress of water
through the drilled passageway.
Figure 3 represents next stage where upon contact with aqueous environment, the swellable
compressed layer swells rapidly. The swelling of the excipjents exerts a pressure surface of
coating having one or more passageways. This leads to opening of the tablet from one surface
leaving the tablet in the form of a cup.
Figure 4 represents the stage where the swellable compressed layer is completely eroded or
disintegrated leaving the active ingredient layer exposed to the aqueous environment. Depending
on the nature of the excipients in the active ingredient composition compressed layer, the active
ingredient is then released for a desired period of time.
Figure 5 describes a stage after the substantially complete release of the active ingredient from
the active ingredient compressed layer. The second inert compressed layer is exposed to the
aqueous environment after the active ingredient layer has eroded or disintegrated. The second
inert compressed layer starts eroding in the intestine causing the coated tablet in the form of cup
to collapse.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a coated tablet having prolonged gastric retention comprising
A. a core comprising two or more compositions in the form of compressed layers wherein at least
one composition comprises a therapeutically active ingredient and rate controlling excipients
B. a coat rupturing system comprising
1. one of aforesaid composition in the form of a swellable compressed layer
comprising a swelling excipient
2. a coating comprising a film former, adjoining said swellable compressed
layer and surrounding said core.
wherein the coating ruptures from at least one of the surfaces when the coated tablet is in an
aqueous environment
C. a second inert compressed layer comprising an inert excipient which is insoluble in gastric
fluids but soluble in at least one region of the intestine, wherein the inert excipient is present in
amounts such that the inert compressed layer retains its size at feast until coated tablet is emptied
from the stomach.
The coated tablet according to the present invention is such that at least one of the dimension i.e
length or breath or thickness of the tablet is more than 15 mm. The tablet retains the initial size at
least along one dimension of the tablet, whereas in the remaining dimensions the size decreases as
the pharmaceutical excipients and/or therapeutically active ingredient are released from the
system.
Upon contact with the gastric environment, the coating on one of the surfaces ruptures, leaving
the sables in the form of a cup from which the active ingredient is released in a controlled manner
from the exposed surface while size along other sides is maintained. Control on the rate of release
of active ingredient is obtained because after the coating ruptures from one surface, substantially
only (hat surface with a defined surface area is available for release of the active ingredient. In
preferred embodiments, the cup shaped coat that is retained is impermeable. In other
embodiments, release of active ingredient by permeation through the coating is only a small
proportion of the overall release of the active ingredient.
7

The core of the coated tablet of the present invention comprises two or more compositions in the
form of compressed layers wherein at least one composition comprises one or more
therapeutically active ingredients.
The therapeutically active ingredients that may be used in the coated tablets of the present
invention may be used include, but are not limited to. alcohol abuse preparations, active
ingredients used for Alzheimer's disease, anaesthetics, acromegaly agents, analgesics,
anliasthmatics, anticancer agents, anticoagulants and antithrombotic agents, anticonvulsants,
antidiabetics antiemetics, antj glaucoma, antihistamines, anti-infective agents, anti park in sons,
and'pJatelet agents, antirheumah'c agents, antispasmodics and anticholinergic agents, antitussives,
carbonic anhydrase inhibitors, cardiovascular agents, cholinesterase inhibitors, treatment of CNS
disorders. CNS stimulants, contraceptives, cystic fibrosis management, doparmne receptor
agonists. endometriosis management, . erectile dysfunction therapy, fertility agents,
gastrointestinal agents, immunomodulators and immunosuppressives, memory enhancers,
migraine preparations, muscle relaxants, nucleoside analogues, osteoporosis management,
parasympathomimetics, prostaglandins, psychotherapeutic agents, sedatives, hypnotics and
tranquillizers, steroids and hormones,
According to one embodiment of the present invention, the composition comprising
therapeutically active ingredient itself be divided into number of layers and fabricated using
conventional multilayer tableting presses. The individual sub layers may be varied in number and
thickness, and each layer may have varying concentrations of the same or different active
ingredients to provide the desired delivery profile(s) of the active ingredient(s). This embodiment
is particularly useful in providing an ascending release profile i.e the active ingredient is released
slowly initially, but as the active ingredient continues to release, the rate of release of the active
ingredient increases.
The composition comprising therapeutically active ingredient may comprise of pharmaceutically
acceptable excipients, which control the release. Such excipients are herein after referred to as
"rate controlling excipients". These rate controlling excipients used in the present invention may
be selected from hydrophilic polymers such as methyl cellulose, hydroxypropyl methylcellulose,
hydroxyethyl cellulose. hydroxypropyl cellulose, hydroxyethyl methylcellulose,
8

carboxymethylcellulose and sodium carboxymethylcellulose; hydrophobic compounds such as
ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, castor wax. carnauba wax, glycerol
monostearate, stearyl alcohol, glycerol behenic acid ester, cetyl alcohol, natural and synthetic
glycerides, waxes, fatty acids, hydrophobic polyacrylamide derivatives, hydrophobic methacrylic
acid derivatives; vinyl pyrrolidone polymers such as polyvinylpyrrolidone and copolymers of
vinyl pyrrolidone and vinyl acetate; alkylene oxide homopolymers; gums of plant, animal,
mineral or synthetic origin; and mixtures thereof. The rate controlling excipients may be used in
an amount ranging from about 2 % to about 99 % by weight of composition comprising the active
ingredient.
One of the embodiments of the present invention uses hydroxypropylmethylcellulose polymers
having viscosity ranging from about 50 to about 25,000 mPa.sec as a rate controlling excipient.
Examples of the HPMC that may be used, include, but are not limited to, Methocels K4M, K15M
and K100M and the like and mixture thereof. In this embodiment, preferably some or all of the
HPMC polymers have a viscosity in the range of from 1000 to 25,000 mPa.sec. Preferably,
HPMC having viscosity of 100,000 cps is used. The percentage of the hydroxypropyl
methylcellulose may range from about 5 % to 50 % by weight of the active ingredient
composition compressed layer.
The composition comprising therapeutically active ingredient may additionally comprise of
conventional excipients such as fillers, lubricants, binders, colorants, dismtegrants, preservatives,
antioxidants and the like.
In one embodiment of the present invention, the coated tablet comprises a "coat rupturing
system" comprising a swellable compressed layer. The swellable compressed layer may
optionally comprise of one or more active ingredients in pharmaceutical acceptable carrier.
The swellable compressed layer comprises swelling excipients, gas generating agents, wicking
agents and mixtures thereof. Preferably the swellable excipient is one that can swell upon
imbibing water to at least twice its original volume.
9

1 he swellable excipient that may be used may be selected from the group comprising cross linked
vinylpyrrolidone plymers such as crospovidone; cellulose and cellulose derivatives such as
carboxyalkyl celluloses, low substituted hydroxypropyl cellulose, crosslmked
carboxyalkylcellulose and their alkali salts; starch and starch derivatives such as pregelatinized
starch,, dried starch. Sodium starch glycoAate; resins such aspoJacriJJin potassium (AmberJJte IRP
88) and the like and mixtures thereof.
The swellable excipient is preferably used in an amount ranging from about 5 % to about 50 % by
weigh! of the swellable compressed layer. Preferably, the swellable excipient that may be used in
an amount ranging from about 2 % to about 40 % by weight of the swellable compressed layer.
Gas generating agents that may be used in the present invention include carbonates such as
calcium carbonate, bicarbonates such as sodium or potassium bicarbonate, sulfites such as sodium
sulfite. sodium bisulfite, or sodium metabisulfite, and the like. These salts may be used alone or
in combination with an acid source as a gas generating couple. The acid source may be an edible
organic acid, a salt of an edible organic acid, acidic components such as acrylate polymers, or
mixtures thereof. Examples of organic acids that may be used include citric acid, malic acid,
succinic acid, tartaric acid, fumaric acid, maleic acid, ascorbic acid, glutamic acid, and their salts,
and mixtures thereof.
The swellable compressed layer may further comprise a wicking agent in an amount ranging from
aboui 0.5% to about 90 % by weight of the swellable composition. Examples of wicking agents
thai may be used include, but are not limited to, colloidal silicon dioxide, kaolin, titanium
dioxidefarmed silicon dioxide, alumina, sodium faaryf salfafe, low molecular weight
polyvinylpyrrolidone, bentonite, magnesium aluminum silicate (Veegum K) and the like and
mixtures thereof. Preferably, the wicking agents used in the pharmaceutical composition of the
present invention include cellulose and cellulose derivatives, colloidal silicon dioxide, and
mixtures thereof.
1 he swellable compressed layer may comprise diluents having wicking action. In certain
embodiments of the present invention co-processed microcrystalline cellulose is used as a
wicking agent. The microcrystalline cellulose is co-processed with silicon dioxide preferably
10

colloidal silicon dioxide. Such a co-processed microcrystalline cellulose (silicified MCC) shows
improved compressibility as compared to standard grades of microcrystalline cellulose. The
silicified microcrystailine cellulose with varying amounts of silicon dioxide is commercially
available under the grand name Prosolv®. Typically the colloidal silicon dioxide content is about
2 % w/w. The most preferred embodiments of the present invention use silicified microcrystalline
cellulose with 2 % w/w of colloidal silicon dioxide. These are available commercially under the
brand name Prosolv SMCC® 90 with a median particle size in the region of 90 /xm and Prosolv
SMCC® 50 with a median particle size in the region of 50 µm.
According to one embodiment of the present invention, the amount of silicified microcrystalline
cellulose that may be used in the present invention may range from about 5 % w/w to about 90 %
w/w, more preferably from about 30 % to about 70 % and most preferably from about 50 % to
about 80 % by weight of the swellable compressed layer.
The swellable compressed layer may also comprise osmogents in an amount ranging from about
0.5% to about 10 % by weight of the swellable compressed layer. Examples of osmogents that
may be used include, but are not limited to, inorganic salts such as magnesium chloride or
magnesium sulfate, lithium, sodium or potassium chloride, lithium, sodium or potassium
hydrogen phosphate, lithium, sodium or potassium dihydrogen phosphate, salts of organic acids
such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate or
sodium ascorbate; carbohydrates such as mannitol, sorbitol, arabinose. ribose, xylose, glucose.
fructose, mannose. galactose, sucrose, maltose, lactose, raffmose; water-soluble amino acids such
as glycine. leucine, alanine, or methionine; urea and the like; osmopolymers selected from the
group consisting of poly(hydroxyaJky] methacrylate) having a molecular weight of 20.000 to
5,000,000: poly (vinylpyrrolidone) having a molecular weight of about 10,000 to 360,000;
poly(vinyl alcohol) having a low acetate content and lightly crosslinked with glyoxal,
formaldehyde, glutaraldehyde and having a degree of polymerization from 2,000 to 30,000;
poly(ethylene oxide) having a molecular weight from 10,000 to 7,8000,000; acidic carboxy
polymers known as carboxypolymethylene or as carboxyvinyl polymers, a polymer consisting of
acrylic acid lightly cross-linked with polyallylsucrose and sold under the trademark Carbopol®,
acidic carboxy polymer having a molecular weight of 200,000 to 6,000,000, including sodium
II

acidic carboxyvmyl hydrogel and potassium acidic carboxyvinyl hydrogel; Cyanamer®
polyacrylamide; and the like, and mixtures thereof.
In a more preferred embodiment of the invention, the swellable compressed layer comprises a
swellable excipient selected from cross linked polyvinyl pyrrolidone and cross linked carboxy
methyl cellulose and a diluent having a wicking action for example, silicified microcrystalline
cellulose,
The swellable compressed layer additionally may comprise other excipients such as surfactants,
lubricants, and other excipients commonly used in the pharmaceutical art.
In one embodiment of the present invention, the coated tablet comprises a "coat rupturing
system" comprising a coating adjoining the said swellable compressed layer and surrounding said
core, wherein the coating ruptures from one of its surfaces.
According to the present invention, the coating comprises a film former. The film former may be
water insoluble polymer. Alternatively, the film former may be a polymer which is insoluble at
pH less than about 4.0 but soluble at or soluble at pH above 7,0,
Examples of water insoluble polymer that may be used include ethyl cellulose, cellulose acetate,
polyvinyl acetate, nitrocellulose, butadiene styrene copolymers, and water insoluble
methacrylate copolymers. Preferably, the water insoluble polymer is selected from the group
consisting of ethyl cellulose, poly(ethyl acrylate, methyl methacrylate. triethylatnmonioethyl
methacrylate chloride), in a ratio 1:2:0.1, (commercially available under the trade names
Eudragil RSI00, Eudragit RS PO, Eudragit RS 30D and Eudragit RS 12.5) and poly (ethyl
acrylale, methyl methacrylate, trimethylammonioethymethacrylate chloride) in a ratio 1:2:0.2
(commercially available under the trade names Eudragit RL100, Eudragit RL PO, Eudragit RL
30D and Eudragit RL 12.5).
Examples of film formers that are insoluble below a pH of about 4.0 but soluble at pH above 7.0
include poly(methacrylic acid, methyl methacrylate) in a ratio 3:1 (Commercially available
under the tradenames Eudragit L 100, Eudragit L 12.5, Eudragit 12.5 P), Poly(methacrylic acid,
12

ethyl acrylate) in a ratio 1:1 (Commercially available under the trade names Eudragit L 30 D-55,
Eudragjl L 100-55, Eastacryl 30 D, Kollicoat MAE 30 D and Kollicoat MAE 30 DP) and poly
(methacrylic acid, methyl methacrylate) in a ratio 1:2 (Commercially available under the trade
names Eudragit S 100, Eudragit S 12.5, Eudragit S 12.5 P). cellulose acetate phthalate,
liydroxypropyt methyl cellulose acetate succinate and the like and mixture thereof.
In .one embodiment of the present invention, the water insoluble polymer included in the coating
may be in the form of an aqueous dispersion. For example, aqueous dispersions of any of the
aforementioned insoluble polymers may be used. Most preferably, an aqueous dispersion of ethyl
cellulose is used,
Suitable aqueous dispersions of ethyl cellulose include those commercially available under the
trade names Aquacoat ECD-30® from FMC Corporation (Philadelphia, USA) and Surelease®
from Colorcon (West Point, PA.). Aquacoat® is an aqueous polymeric dispersion of
elhylcellulose and contains sodium lauryl sulfate and cetyl alcohol while Surelease® is an
aqueous polymeric dispersion of ethyl cellulose and contains dibutyl sebacate, oleic acid,
ammoniated water and fumed silica.
The coat may be applied to a weight gain of about 5 % to about 20 % by weight, preferably from
about 8 % to about 15 % by weight of the core.
According to the present invention the coat is substantially impermeable to the passage of the
active ingredient. Upon contact with the aqueous environment, the coating is ruptured from at
least one of its surfaces and thereby release of the active ingredient is enabled. The coat is
ruptured from at least one of the surfaces by the action of a coat rupturing system.
The coat rupturing system comprises the swellable compressed layer and the coating, which is
defective or reactive as descried in our co-pending application WO2005/039481. Preferably, the
coating that ruptures from at least one of the surfaces is selected from the group consisting of a
coating comprising a film former and a pore forming agent, a coating comprising a film former
and optionally a plasticizer wherein the type and amounts of the film former and optionally the
plaslicizer are selected to form a coating capable of rupturing upon swelling of the swellable
13

compressed layer in the core; and a coating comprising a film former and one or more
passageways.
When the coating has one or more passageways, they may be created by techniques such as
manual, laser drilling and the like. A passageway may be drilled in the vicinity of the swellable
compressed layer so that upon contact with aqueous environment, water enters through the drilled
passageways, the swellable compressed layer swells and exerts pressure on that surface and
eventually ruptures the coating from the drilled surface.
The diameter of the pore is selected such that no substantial delay occurs in rupturing of the coat.
Preferably, the pore diameter is in the range from about 500 ®m to about 1000 ®m. The term
"without a substantial delay" as used herein means that the active ingredient release is initiated
from the coated tablets of the present invention within 0 to 60 minutes from the time the core
contacts an aqueous environment, preferably within 0 to 20 minutes, and most preferably within 0
to 5 minutes.
In another embodiment of the present invention the coating comprises a film former and a pore-
forming agent. A pore forming agent may be defined herein as an agent that forms micro porous
coatings formed in situ by dissolution upon exposure to an aqueous environment of use. Pores
may also be formed in the coating by gas formation. The pore forming agent may be a solid or a
liquid. Pore forming-agents that may be used include, water-soluble compounds that have
molecular weight of less than about 2000 Daltons and hydrophilic polymers.
The pore forming agents that may be used in the present invention may be selected from the
group consisting of alkali metal salts, alkaline earth metals, transition metal salts, organic
compounds and the like.
The examples of alkali metal salts include, but not limited to, sodium chloride, sodium bromide,
sodium carbonate, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate,
sodium citrate, potassium nitrate, and the like. Examples of alkaline earth metal salts include, but
not limited to, calcium phosphate, calcium nitrate, calcium chloride, and the like. Examples of
transition metal salts include, but not limited to, ferric chloride, ferrous sulfate, zinc sulfate,
14

cupric chloride, manganese fluoride, manganese fluorosilicat£, and the like. Examples of organic
aliphatic oils include, but not limited to, diols and polyols, aromatic oils including diols and
polyols, and other polyols such as polyhydric alcohol, polyjilkylene glycol, polyglycol and the
like.
Examples of organic compounds that may be used as pore forming agent, include, but not limited
to. monosaccharides, polysaccharides, sugar alcohol and the like. As used herein, the
monosaccharides contain from 3-6 carbon atoms and include aldoses and hexoses. Examples of
monosaccharides include glyceraldehydes, erythrose, threose, ribose, arabinose, xylose, allose,
alirose, glucose, mannose, galactose, talose, erythrulose, ribulose, xylulose, psicose, fructose,
sorbose. tagatose, and the like. The monosaccharides may exist as either the D or L isomer,
although the D-isomer is preferred. Examples of disaccharides include maltose, lactose, sucrose
and the like. The most preferred pore forming agent used in the coating composition of the
present invention is selected from sugar alcohols, most preferably mannitol.
Examples of hydrophilic polymers that may be used as pore forming agents are selected from the
group comprising of vinyl polymers, cellulose derivatives, polyethylene glycols and the like and
mixtures thereof.
Examples of the vinyl polymers that may be used as pore forming agent include, but are not
limned to, poly vinyl pyrrolidone, polyvinyl alcohol and the like and mixtures thereof.
When the polymer is polyvinyl pyrrolidone (PVP) it is preferred that the PVP has an average
molecular weight of about 2000 to about 3 million and more preferably from about 7000 to about
1.500.000. Most preferred PVP has an average molecular weight of about 40,000 (such as
Povidone K30) or about 1,500,000 (such as Povidone K90). Both Povidone K30 and K90 are
commercially available from BASF, Midland, Michigan.
Examples of the cellulose derivatives that may be used as hydrophilic polymers include, but are
not limited to. methyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxyethyl
cellulose and mixtures thereof. Preferably, low viscosity grade cellulose derivatives are used. The
low viscosity grade cellulose derivatives that may be used may have a viscosity ranging from
15

about 2 to about 50 mPa. These are the typical viscosity values for 2% (w/v) aqueous solutions
measured at 20°C. Examples of low grade viscosity hydroxy propyl methyl cellulose derivatives
that may be used include, but not limited to. E3 Low viscosity (LV) grade having viscosity of 2.4
to about 3.6, E5 LV having viscosity of 4 to about 6, £6 having viscosity ranging from 5 to 7,
El5 having viscosity ranging from 12 to 18; E50 having viscosity ranging from 40 to 60; K.3
having viscosity ranging from 2.4 to 3.6 and the like and mixtures thereof. Other cellulose
derivatives that may be used include, but not limited to, low substituted hydroxy propyl cellulose
(L-HPC). hydroxyelhyt cellulose (HEC). HEC is known under the brand name of Natrosol, is
available hydroxyethyl cellulose is available in a wide range of viscosity types; e.g., Cellosize is
manufactured in 1 ! regular viscosity grades. Hydroxyethyl cellulose grades differ principally in
(heir aqueous solution viscosities which range from about 2 to about 20, 000 mPa s for a 2% w/v
aqueous solution. Two types of Cellosize are produced, a WP-type, which is a normal-dissolving
material, and a QP-type, which is a rapid-dispersing material. Generally, low viscsotiy grades are
preferred in the present invention. Examples of low viscosity grade hydroxy ethyl cellulose
include, but are not limited to. commercially available grades under the tradenames WP 02 grade,
WP 09 grade.
Examples of the polyethylene glycol that may be used include, but are not limited to,
polyethylene glycol having average molecular weights ranging from about 1,000 to 6000.
The pore forming agent is present in an amount ranging from about 5% (w/w) of the dry weight
of the coating to not more than about 50 % of the dry weight of the coating (w/w). More
preferably, it is present from about 6% to about 40% of the coating (dry weight) and still more
preferably from about 10% 10 about 20% of the coating (dry weight). In addition, the dry weight
ratio of the water insoluble polymer to the pore forming agent ranges from about 1: 9 to about
9:1; and even more preferably from about 6:4 to about 4: 6 and most preferably from about 7:3 to
about 8:2.
In one embodiment of (he present invention, the coat rupturing system comprises a coating
comprising a film former and optionally a plasticizer wherein the type and amounts of film
former and optionally plasticizer are selected to form a coating capable of rupturing upon
swelling compressed layer in the core.
16

The type and amount of plasticizer used in the coating composition may depend upon the type of
film forming agent used. The amounts and type are selected to form a coating capable of
rupturing upon swelling of the swellable compressed layer in the core. Varying amounts of
plasticizers may cause weakness in the coating thereby allowing rupturing of the coat. The low
amount of plasticizers may make the coating brittle and therefore susceptible to breaking upon
contact with the aqueous environment.
The plasticizers that are used in coating are generally the ones conventionally known in the art.
For example, the plasticizers (hat may used include, but are not limited to, diethylphthalate.
iriethyl citrate, triethyl acetyl citrate, triacetin, tributylcitrate, polyethylene glycol, giycerol.
vegetable and mineral oils, maltodextrin and mixtures thereof, and the like. The plasticizer may
be present in the coating in amounts ranging from about 0.01% to about 25% by weight and more
preferably from about 5 % to about 15% by weight based on the dry weight of the coating.
The coating contains at least about 5 % solids with the remainder being water. Preferably, the
coaling contains from about 5 % to about 30 % solids and more preferably from about 10 % to
about 25 % by weight of the solids.
Besides the water insoluble polymer, pore forming agent and the water, the coating may also
contain other additives normally found in coatings used in the pharmaceutical art. These include
plasticizers, wetting agents, lubricants, coloring agents commonly used in the pharmaceutical art.
The coloring agents are added to provide elegance and product distinction. Suitable ingredients
for providing color to the formulation include titanium dioxide and color pigments, such as iron
oxide pigments, FD&C Yellow No. 6, FD&C Red No. 2, FD&C Blue No. 2, food lakes and the
like. If present, they are present in amounts ranging from about 0.1% to about 20% by dry weight
of the coating composition (w/w) and more preferably less than about 3% by dry weight (w/w) of
the coating.
The coating may optionally include a lubricant. Examples of suitable lubricants include talc,
calcium stearate, colloidal silicon dioxide, glycerin, magnesium stearate, aluminum stearate, or a

17

mixture of any two or more of the forgoing, and the like. The lubricant may be present in amounts
ranging from about 0.01% to about 10% by dry weight of the coating.
According to the present invention, the coated tablet comprises a second inert compressed layer
comprising an inert excipient which is insoluble in gastric fluids but soluble in at least one region
of the intestine, wherein the inert excipient is present in amounts such that the inert compressed
layer retains its size at least until coated tablet is emptied from the stomach.
The amount of inert excipient may vary from about 5 % to about 90 % of the total weight of the
second compressed layer, preferably from about 10 % to about 50 % of the total weight of the
second compressed layer.
According to the present invention, the inert excipient is insoluble in gastric fluids but soluble in
at least one region of the intestine. In one of the preferred embodiment the inert excipient is pH
dependent polymer.
Examples of the pH dependent polymer that may be used include, but are not limited to, cellulose
acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate and
polymethacrylate and the like and mixtures thereof.
Examples of polymethacrylate that may be used include, but are not limited to, Eudragit L and S.
These are generally referred to as methacrylic acid copolymers and are anionic co polymerization
products of methacrylic acid and methyl methacrylate. The ratio of free carboxyl groups to esters
is approximately ): i in Eudragit L and 1: 2 in Eudragit S. Both polymers are readily soluble in
neutral to weakly alkaline conditions (pH 6-7) and forms salts with alkalis. These polymers are
available as solution with or without plasticizers. free flowing powders with at least 95 % of dry
polymers.
Another grade of Eudragit polymer is Eudragit L 30 D-55. These are available as an aqueous
dispersion of an anionic copolyiner based on methacrylic acid and ethyl acrylate. The ratio of free
carboxyl groups to ester groups is 1:1. Films prepared from these copolymers dissolve above pH
5.5 forming salts with alkalis, thus affording coating which is insoluble in gastric media, but

18

soluble in the small intestine. Eudragit L 100-55 is a white, free flowing powder, which is
redispersible in water to form a latex, which has properties similar to Eudragit L 30 D-55.
According to one embodiment of the present invention, the second inert compressed layer may
optionally comprise hydrophobic materials. Examples of the hydrophobic material that may be
used include, but are not limited to, glyceryl behenate, hydrogenated castor oil and the like and
mixtures thereof.
The coated tablets of the present invention may be any suitable shape, such as round, oval,
biconcave, hemispherical or any polygonal shape such as square, rectangular, pentagonal and the
like.
The tablet core may be obtained by the conventional processes, such as wet, dry granulation or
direct compression. For example, the therapeutically active ingredient composition is prepared
first. When the therapeutically active ingredient layer composition is prepared by wet granulation
active ingredient is mixed with other pharmaceutically acceptable excipients and granulated.
followed by screening and drying of the damp mass. The dried mass may be screened, lubricated
and compressed. Dry granulation can be done by two processes: (1) slugging, which involves
mixing the active ingredient with other the excipients, slugging, dry screening, lubrication and
compression, or (2) roller compaction process. Direct compression involves compressing the
physical mixture therapeutically active ingredient with the excipients.
The swellable compressed layer may be prepared by conventional methods known in the
pharmaceuticsl; art. For example, the swelling agents, diluents and other additives may be mixed
and further processed by either dry, wet granulation or direct compression.
The compositions for example, the therapeutically active ingredient compressed layer and the
swellable compressed layer and the inert compressed layer compositions are granulated, the
granules of the individual compositions are compressed to form a trilayer tablet using a rotary
compression. When the compositions are processed by direct compression, the blends of the
compositions respectively, may be compressed using a rotary press.
19

The coating of the tablet core is carried out by art-recognized techniques. The water insoluble
polymer in the aqueous dispersion is either commercially obtained or is prepared using known
emulsion polymerization techniques.
In one embodiment of the present invention, the coating is drilled by mechanical means either
manual drilling or by laser drilling by techniques known in the art. Optionally, when a pore
forming agent is used, a pore-forming agent is mixed with water, if further dilution is desired, and
mixed until the pore forming agent is completely dissolved in the coating dispersion. The coating
composition may be prepared by dissolving the pore forming agent in water and adding the
dispersion of the water insoluble polymer to it, and then mixing the two together until the water
soluble compound is dissolved in the aqueous dispersion. Alternatively, the coating dispersion
may be prepared by adding water to the dispersion of the water insoluble polymer and then
dissolving the pore-forming agent, in the diluted dispersion. Whichever way made, the coating
has a solid content ranging from about 5 % to about 25 % w/w, preferably from about 10 % to
about 20 %, more preferably from about 10 % to about 15% w/w.
The following example does not limit the scope of the invention and are used as illustrations.
20

EXAMPLE
TABLE 1: SWELLABLE COMPRESSED LAYER
Ingredients mg per tablet % \v/w of the swell able
compressed layer
Carbidopa mohohydrate equivalent to carbidopa
anhydrous 10.0 2.8
Levodopa 40.0 11.4
Silicified Microcrystalline Cellulose (Prosolv
SMCC 90) 212.40 60.6
Crospovidone 60.00 17.14
Colloidal silicon dioxide 7.50 2.14
Polyvinvl pyrrolidone 15.00 4.28
FDC Blue No.1 Lake 1.20 0.34
Magnesium stearate 2.40 0.68
Magnesium stearate 0.75 0.21
Talc 0.75 | 0.21
Tola! weight 350.0
TABLE 2: THERAPEUTICALLY ACTIVE INGREDIENT COMPRESSED LAYER

Ingredients mg per tablet % w/w of (he active
ingredient compressed layer
carbidopa 40.0 7.9
levodopa 160.0 31.68
Hydroxypropyl methyl cellulose
HPMC K100 Viscosity grade (lOO.OOO) * K 100 M 50.0 9.9
Mannitol SD 200 206.0 40.79
Polyvinyl pvrrolidone K30 30.0 5.94
Colloidal silicon dioxide 8.0 1.58
Talc 5.0 0.99
Maanesium stearate 6.0 1.18
Total weieht 505.0
TABLE 3: INERT COMPRESSED LAYER

Ingredients mg per tablet % w/w of the
layer inert compressed
Microcrvslalline Cellulose (Aviccl PH 102) 224.19 63.15
Methacrylate copolymer tvpe C (Eudragii LI 00 55) 71.0 20
Polyvinvl pvrrolidone K30 53.25 15
Talc 2.66 0.74
Maenesium stearate 2.66 0.74
FD&CYellowNo.6Lake 1.24 0.34
Total weight 355.00
The active ingredients along with the inactive ingredients are mixed and subjected to slugging.
The slugs were mixed with magnesium stearate. talc and compressed.
21

The weighed amounts of active ingredient were mixed with colloidal silicon dioxide. The blend
was sieved and passed through 40 mesh. The blend was mixed with HFMC K100 LV, Mannitol
SD200 and PVP K 30 and sifted again. This blend was granulated with purified water in the
rotary mixer grinder. The granules were dried and milled and extragranular additives added
further.
The pigment and MCC were mixed and sifted through # 60. Eudragit LI00 55, PVP K30 &
remaining qty of MCC were mixed together and sifted through # 40. Blend of talc & magnesium
stearate was passed through # 60. All the blends were mixed together in a double cone blender
and mixed for 10 min.
The compositions of all the three layers were used for compression. The compression was
performed on a trilayer compression machine at a target weight of about 1210mg
TABLE 4: COATING

Ingredients mg per core tablet of the core Percent w/w dry
weight
Aquacoat EC30 D* 77.52
Ethyl cellulose 20,93 69.21
Sodium lauryl sulphate 0.7752 2.56
Ceryl alcohol 1.55 5.12
Dibutyl sebacate 5.81 19.21
Trie thyl citrate 1.16 3.83
water 15.15
Aqiuicoat EC 30 D is the commercially available ethyl cellulose aqueous dispersion containing 27 % w/v of
crhyl cellulose, I % SLS and 2 % cetyl alcohol.
The trilayer tablet prepared was coated with ethyl cellulose aqueous dispersion to achieve a
weight gam of approximately 12 % of the weight of the core tablet. The coated tablets were
drilled on the surface in the immediate vicinity of the swellable compressed layer.
The approximate size of the coated tablet is 19.4 mm (length). 9.8 mm (breadth) and 9.5 mm in
thickness.
When the drilled coated tablets are placed in aqueous medium, the coating ruptured in about 5
minutes to about 10 minutes exposing the therapeutically active ingredient composition to the
gastric environment.
22

The coated tablets were subjected to in vitro dissolution testing in simulated gastric fluids (0.01 N
hydrochloric acid) at 100 rpm and 37 °C using Type 1 USP dissolution apparatus.
TABLE 5: in vitro dissolution data for carbidopa and levodopa

Time in Hours % released

Carbidopa levodopa
0 0 0
1 22 24
2 31 33
4 52 57
6 76 82
8 86 95
23

We Claim:-
1. A coated tablet having prolonged gastric retention comprising
A. a core comprising two or more compositions in the form of compressed layers
wherein at least one composition comprises a therapeutically active ingredient and
rate controlling excipients
B. a coat rupturing system comprising
1 .one of aforesaid composition in the form of a swellable compressed
layer comprising a swelling excipient
2. a coating comprising a film former adjoining said swellable compressed
layer and surrounding said core,
wherein the coating ruptures from at least one of the surfaces when the coated tablet
is in an aqueous environment
C. a second inert compressed layer comprising an inert excipient which is insoluble in
gastric fluids but soluble in at least one region of the intestine, wherein the inert
excipient is present in amounts such that the inert compressed layer retains its size at
least until coated tablet is emptied from the stomach.
2. A coated tablet as claimed in claim 1 wherein at least one of the dimensions of the
tablet is more than 15 mm.
3. A coated tablet as claimed in claim 1 wherein the coating that ruptures from at least
one of the surfaces is selected from the group consisting of
a. a coating comprising a fiim former and a pore forming agent
b. a coating comprising a film former and optionally a plasticizer wherein the type
and amounts of the film former and optionally the plasticizer are selected to
form a coating capable of rupturing upon swelling of the swellable compressed
layer in the core; and
c. a coating comprising a film former and one or more passageways.
4. A coated tablet as claimed in claim 1 wherein the coating is impermeable to the active
ingredient.
24

7. A coated tablet as claimed in claim 6 wherein the ethyl cellulose is applied to a weight gain
ranging from about 8 % to about 15 %.
8. A coated tablet as claimed in claim 1 wherein the swellable compressed layer comprises
swelling excipients, gas generating agents, wicking agents and mixtures thereof.
9. A coated tablet as claimed in claim 8 wherein the swelling excipients are selected from the
group comprising croscarmellose, crospovidone, sodium starch glycolate, pregelatinized starch,
dried starch, low-substituted hydroxypropyl cellulose and mixtures thereof.
10. A coated tablet as claimed in claim 8 wherein wicking agent is selected from the group
comprising magnesium aluminium silicate, silicified microcrystalline cellulose and mixtures
thereof.
11'. A coated tablet as claimed in claim 1 wherein the inert excipient in the second inert
compressed layer is a pH dependent polymer.
12. A coated tablet as claimed in claim 11 wherein the pH dependent polymers are selected from
the group consisting of methacrylates and its derivatives.
25
Dated this 3rd day of November 2006