FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULESV 2003
Complete specification
[See Section 10 and rule 13]

1 Title of the Invention.
"PHARMACEUTICAL COMPOSITION "
2 Applicant (s)
Applicant Name Torrent Pharmaceuticals Ltd.

Nationality Indian

Address Torrent House Off Ashram Road
Near Dinesh Hall
Ahmedabad - 380009. Gujarat
The following specification particularly describes the invention and the
manner in which it is to be performed.


PHARMACEUTICAT, COMPOSITION
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition of practically water
insoluble or low water soluble compounds containing catechol moiety by enhancing
the solubility of such compounds using one or more alkalising agent.
The present invention also relates to a process for preparing such pharmaceutical
composition
BACKGROUND OF THE INVENTION
Low-solubility drugs often show poor bioavailability or irregular absorption, the
degree of irregularity being affected by factors such as dose level, fed state of the
patient, and form of the drug. Increasing the bioavailability of low-solubility drugs
has been the subject of much research. Increasing bioavailability hinges on improving
the concentration of the drug in solution to improve absorption.
It is known that many low-solubility drugs can be formulated so as to increase the
maximum concentration of the drug that will dissolve in an aqueous solution in in-
vitro tests. It has been shown that when such forms are tested in vivo they can
enhance the relative bioavailability of the drug, presumably by enhancing, at least
temporarily, the concentration of dissolved drug present in the gastrointestinal (GI)
tract.
Another approach is that some low-solubility drugs may be formulated in highly
soluble salt forms that provide temporary improvements in the concentration of the
drug in a use environment relative to another salt form of the drug. An example of
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such a drug is sertraline, which in the lactate salt rpm has a higher aqueous solubility
at pH 3 than the HC1 salt form. Use of water Soluble acid addition salt of poorly
soluble drug is disclosed in US Patent 5,441,747.
It is known that other drug form known to provide increased concentrations in
solution of low-solubility drugs consists of drug in a hydrate or solvate crystalline
form of the drug. Such forms often have higher aqueous solubility relative to the
lowest solubility, crystalline form and, therefore, provide higher concentrations of
drug. Polymorphs comprise another drug form that temporarily provides increased
concentrations in solution. Some polymorphs, also referred to herein as "high-energy
crystalline forms," have higher aqueous solubility and therefore can provide enhanced
aqueous concentration of the drug relative to other crystal structures and relative to
the equilibrium concentration.
It is also well known that the amorphous form of a low-solubility drug that is capable
of existing in either the crystalline or amorphous form may also temporarily provide a
greater aqueous concentration of drug relative to the equilibrium concentration of
drug in a use environment. It is believed that the amorphous form of the drug
dissolves more rapidly than the crystalline form, 0ften dissolving faster than the drug
can precipitate from solution. As a result, the amorphous form may temporarily
provide a greater-than equilibrium concentration of drug-
Another method that can temporarily provide a greater than equilibrium drug
concentration is to include a solubilizing agent Such as citric acid, etc. in the drug
form. Such solubilizing agents promote the aqueous solubility of the drug. An
example of the use of a solubilizing agent with a drug to increase aqueous solubility
is the use of solubilizing agents with sertraline. As disclosed in PCT Application No.
99/01120, when sertraline is co dissolved in aqueous solution with a solubilizing
agent, for example, citric acid, the solubility of sertraline is dramatically increased.
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Yet another technique for temporarily achieving a greater than equilibrium
concentration of drug in a use environment is to formulate the drug as an aqueous or
organic solution. For example, drug can be dissolved in polyethylene glycol (PEG) or
an aqueous solution of PEG to which an acid or base may be added or the drug may
be dissolved in an aqueous solution of an acid or base. Alternatively, the drug can be
dissolved in a pharmaceutically acceptable organic liquid such as glycerol, mono-, di-
, or triglycerides, fats or oils.
Another approach to increase the bioavailability of low-solubility drugs has involved
forming amorphous dispersions of drugs with polymers. Examples of attempts to
increase drug concentration by forming a dispersion of the drug with a polymer
include Lahr et a!., U.S. Patent 5,368,864, Kanikanti et al., U.S. Patent 5,707,655 and
Nakamichi et al., U.S. Patent 5,456,923. However, creating an amorphous dispersion
of a drug and polymer(s) does have some drawbacks. For example, some drugs may
degrade at the elevated temperatures used to form some dispersions. Some processes
use organic solvents, which must be thoroughly removed to avoid drug degradation.
Increasing drug solubilization by using combinations of drug and polymer has also
been described. For example, Martin et al., U.S. Patent 4,344,934 mixed poorly-
soluble drugs with polymers such as hydroxypropyl methyl cellulose (HPMC) and
added an aqueous surfactant solution to the drug-polymer mixture. While this results
in improved dissolution, there is only slight enhancement of drug concentration
relative to the equilibrium concentration. Particle size reduction of active principle
may also improve the bioavailabilty.
It is desirable that active pharmaceutical ingredient is released from the oral
composition as soon as possible after ingesting it. This can normally be achieved by
using a solublisation enhancing agent in the pharmaceutical composition. The
solublisation enhancing agent may be a disintegrant, surface active agent or any other
agents that enhance the solublisation. There is vast selection of different solublisation
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enhancing agents, including disintegrants, on the market, which have different
chemical and physical characteristics. When selecting the best solublisation
enhancing agent to be vised in the pharmaceutical composition in combination with

active agent, numerous factors have to be considered., e.g. the chemical and physical
characteristics of the active agents , and solublisation enhancing agent, the chemical
and physical characteristics of the auxiliary agents, such as diluents and binder, the
method of preparing the composition, etc.
Various compound containing catechol moiety like entacapone, nitecapone, tolcapone
or a pharmaceutically acceptable salt thereof, are used as active pharmaceutical
ingredient are practically insoluble in water. Because of this property, dissolution of
the product & bioavailability is always a challenge to develop the product in
formulation.
Entacapone is an inhibitor of catechol-O-methyltransferase (COMT), used in the
treatment of Parkinson's Disease as an adjunct to levodopa / carbidopa therapy.
Formulations of solid medicinal forms with the active ingredient entacapone,
nitecapone or pharmaceutically acceptable salts thereof have already been described
in US6599530. It was found that croscarmellose sodium can be used in an amount of
at least 6% by weight of the composition to resolve the poor dissolution of
entacapone, nitecapone or pharmaceutically acceptable salts thereof. Croscarmellose
sodium is required for satisfactory dissolution as compared to other common
dissolution-improving agents such as sodium lauryl sulphate, sodium starch
glycolate, starch, pregelatinized starch, microcrystalline cellulose or mannitol.
According to this invention, the poor dissolution problem of entacapone can be
resolved by using croscarmellose sodium in an amount of at least 6% by weight of
the composition. This patent justifies use of croscarmellose sodium in the marketed
product.
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Entacapone Tablet is available in US and elsewhere under the ^trade name of
COMTAN®
The inactive ingredients of the COMTAN® Tablet are microcrystalline cellulose,
mannitol, croscarmellose sodium, hydrogenated vegetable oil, hydroxypropyl
methylcellulose, polysorbate 80, glycerol 85%, sucrose, magnesium stearate, yellow
iron oxide, red oxide, and titanium dioxide. Physician's Desk Reference, 59th ed., pp.
2291-2295 (2005)
PRIOR ART
Among the various compounds, entacapone and nitecapone having catechol moiety
are described in U.S. Pat. No. 5,446,194 as catechoI-O-methyltransferase (COMT)
inhibitors. Enteral and parenteral routes of administration are discussed in U.S. Pat.
No. 5,446,194.
Crosslinked cellulose derivative like croscarmeHose sodium enhances the dissolution
of Entacapone in oral compacted dosage form is described in WO 00/15196. The
invention relates to an oral compacted composition comprising entacapone,
nitecapone, or a pharmaceutically acceptable salt thereof, and croscarmeHose sodium
(Ac-Di-Sol) as a dissolution-enhancing agent. It was found that crosslinked cellulose
derivative like croscarmeHose sodium can be used in an amount of at least 6% by
weight of the composition to resolve the poor dissolution of entacapone, nitecapone
or pharmaceutically acceptable salts thereof. According to this invention
croscarmeHose sodium is required for satisfactory dissolution as compared to other
common dissolution improving agents such as sodium lauryl sulphate, sodium starch
glycolate, starch, pregelatinized starch, microcrystalline cellulose or mannitol.
According to this invention, the poor dissolution problem of entacapone can be
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resolved by using croscarmellose sodium in an amount of at least 6% by weight of
the composition.
US20060222703 discloses pharmaceutical compositions of entacapone, levodopa &
carbidopa along with pharmaceutical excipients, wherein the excipients are long
chain polymers having an equilibrium moisture content of atleast 2% and the
preparation methods.
In a research article, titled as "Effect of aqueous solubility and dissolution
characteristics on oral bioavailability of entacapone" (Jouko Savolainen et al. Drug
Development Research 2000; 49 {Issue 4}; pages 238-244) discusses about effect of
hydroxypropyl-β-cyclodextrin (HP-β-CD) on entacapone. This study shows
complexation of entacapone with HP-β-CD (10%w/v) increases the aqueous
solubility of entacapone 12 fold and 85 fold at pH 3,0 and at pH 5,0, respectively.
The present inventors have surprisingly found that pharmaceutical compositions of
the poorly soluble compounds containing catechol moiety such as Entacapone,
nitecapone, tolcapone when formulated along with alkalising agent, and
manufactured by a process such as wet granulation exhibited excellent dissolution
characteristics and were found to be comparable with respect to the marketed
formulation.
It was further surprisingly found that Entacapone could be formulated without using
crosslinked cellulose derivative, or binder or disintegrant without affecting the
dissolution characteristics of the drug.
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OBJECTS OF THE INVENTION
It is an object of the present invention to provide a pharmaceutical composition of
practically water insoluble or low water soluble compounds containing catechol
moiety by enhancing the solubility of such compounds by using one or more
alkalising agent.
Another object of the present invention is to provide a simple granulation process,
like wet granulation for manufacturing of solid oral dosage form for practically water
insoluble or low water soluble compounds containing catechol moiety.
Yet anothei object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, to achieve desired dissolution profile.
Yet another object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, without incorporating crosslinked cellulose derivative, to achieve
desired dissolution profile.
Yet another object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, without incorporating binder, to achieve desired dissolution profile.
Yet another object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, without incorporating disintegrant, to achieve desired dissolution
profile.
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Yet another object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, without incorporating crosslinked cellulose derivative, disintegrate
and binder, to achieve desired dissolution profile.
Yet another object of the present invention is to provide pharmaceutical compositions
comprising active ingredient such as catechol derivatives like entacapone, nitecapone
and tolcapone in combination with levodopa, carbidopa or other such compounds.
either separately or in a fixed dose combination thereof.
Further object of the present invention to provide process of preparing pharmaceutical
composition of practically water insoluble or low water soluble compounds
containing catechol moiety.
SUMMARY OF THE INVENTION
Thus according to the first aspect of the present invention there is provided a
pharmaceutical composition and its manufacturing process by solubility enhancement
of practically water insoluble or low water soluble compounds containing catechol
moiety by using one or more alkalising agent.
According to second aspect of the invention the pharmaceutical dosage form is in the
form of a tablet, capsule, powder or pellets or parenteral comprising catechol moiety
and alkalising agent.
Further, the present invention also provides a solid dosage form of compounds
containing catechol moiety, alkalising agent(s), and one or more adjuvants, optionally
without using binder and / or disintegrant and a process for preparation of the same.
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Additional objects and advantages of the invention will be set forth in part in the
description which follows, and in part will be obvious from the description, or may be
learned by practice of invention. The objects and advantages of the invention will be
realized and attained by means of the elements and combinations particularly pointed
out in the appended claims.
It is to be understood that both the foregoing general description and the following
detailed description are exemplary and explanatory only and are not restrictive of the
invention, as claimed.
DETAILED DESCRIPTION OF THE INVENTION
Applicants have found that alkalising agent is effective for increasing the dissolution
rate of practically water insoluble or low water soluble compounds containing
catechol moiety. Present invention relates to a pharmaceutical composition of such
compounds by enhancing the solubility using one or more alkalising agent.'
The present invention also teaches a process for preparing said composition.
An oral dosage form wherein a mixture of an active compound containing catechol
moiety was granulated with alkalising agent(s), then mixed with one or more
auxiliary agent, and further the blends are tableted or enclosed in capsule. The best
dissolution enhancing agent is the one that releases the active ingredient from the
dosage form as fast as possible.
Direct compression may be done by blending active ingredient with alkalising agent
then mixing with one or more auxiliary agents, and further the blends may be tableted
or lubricated blend can be filled in capsule.
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Applicants found that alkalising agent is more efficient in releasing active ingredient
from the oral dosage form than other common dissolution improving agents, such as
sodium lauryl sulphate, polysorbate, starch, mannitol, lactose, pregelatinised starch,
microcrystalline cellulose.
The term "drug" or "active ingredient" refers to an agent, active ingredient compound
or other substance, or compositions and mixture thereof that provide some
pharmacological, often beneficial, effect. Reference to a specific active ingredient
shall include where appropriate the active ingredient and it's pharmaceutically
acceptable salts.
The term "dosage form" denotes any form of the formulation that contains an amount
sufficient to achieve a therapeutic effect.
The term "Practically water insoluble" refers having a solubility of about more than
10,000 parts of solvent required to solubilize one part of drug.
The term "Low water soluble" refers having a solubility of about 30 to 10000 parts of
solvent required to solubilize one part of solute.
Compounds having catechol moiety refers to the active ingredient. Examples of
compounds having catechol moiety comprises of but not limited to entacapone,
nitecapone tolcapone, tretoquinol apomorphine, melevodopa, dobutamine,
dopexamine, droxidopa, fenoldopam, keracyanin, methyldopa, papaveroline and their
pharmaceutically acceptable salts, esters, polymorphs, hydrates, solvates, enantiomers
or mixtures thereof.
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Pharmaceutical Composition
A pharmaceutical dosage form of a tablet or capsule or parenteral which comprises a
pharmaceutically effective amount of active ingredient containing catechol moiety
and alkalising agent.
The present invention also provides a process for preparation of solid dosage form
preferably tablet or capsule of catechol derivative with alkalising agent and one or
more adjuvants.
Pharmaceutical composition according to the present invention is preferably in the
form of a tablet or capsule or parenteral. The active ingredient used in the present
pharmaceutical composition is catechol derivative, which is subjected to alkaline
enviroment, dried and optionally sieved.
The solid dosage form tablet or capsule of the present invention is prepared using
active ingredient and alkalising agent i.e.,.catechol derivative with alkalising agent
and pharmaceutically acceptable excipients selected from the group comprising of
diluents, lubricants, glidants and other phannaceutically acceptable excipients or
adjuvants but without a disintegrant more particularly without a crosslinked cellulose
derivative.
The alkalising agent(s), which are to be used in accordance with the invention, are
now described. It is only required of such alkalising agents to show basicity (pH of
not less than 7) when they are in the form of a 1% aqueous solution or suspension
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Alkalising agent may be selected from the group comprising sodium dihydrogen
phosphate disodium dihydrogen phosphate, trisodium pho'sphate, sodium bicarbonate,
sodium carbonate, sodium hydroxide, potassium hydroxide, potassium hydrogen
phosphate , dipotassium hydrogen phosphate, tripotassium phosphate and other
materials known for such property, "providing alkaline environment" is a process in
which the catechol derivative is mixed with alkalising agent(s). The mixing can be
dry or wet with suitable vehicle, if required. Alkalising agent in the dosage form
ranges from 0.4% to 52.0% by weight.
Diluents may be selected from the group comprising of mannitol, microcrystalline
Cellulose, lactose, starch, dibasic calcium phosphate anhydrous, tribasic calcium
phosphate, kaolin, sucrose, precipitated calcium carbonate, sorbitol, maltodextrin,
powdered cellulose, micro crystalline cellulose and other materials known for such
property. Diluents in the dosage form ranges from 0% to 78.0% by weight.
Lubricants may be selected from the group comprising of stearic acid, sodium stearyl
fumarate, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc
stearate, hydrogenated castor oil, silica, colloidal silica, comstarch, calcium silicate,
magnesium silicate, silicon hydrogel and other materials known for such property.
Lubricants in the dosage form ranges from 0% to 3.0% by weight.
Binders may be selected from the group comprising of polyvinylpyrrolidone,
hydroxypropyl methylcellulose, acacia, alginic acid, hydroxy propyl cellulose,
carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid
glucose, methylcellulose, pregelatinized starch and other materials known to one of
ordinary skill in the art. Binders in the dosage form ranges from 0% to 5.0% by
weight.
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Glidants may be selected from the group comprising of colloidal silicon dioxide,
colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal
silicon, silicon hydrogel and other materials known for such property. Glidants in the
dosage form ranges from 0% to 2.0% by weight.
The pharmaceutical composition may optionally be coated with functional and / or
non-functional layers comprising film-forming polymers, if desired.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl
methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinyl acetate
methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose,
hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate,
cellulose acetate phthalate, cellulose acetate trimellitate; waxes; methacrylic acid
polymers and the like. Alternatively, commercially available coating compositions
comprising film-forming polymers marketed under various trade names, such as
Opadry may also be used for coating. Film-forming polymer in the dosage form
ranges from 1.5% to 4.0% by weight.
Other pharmaceutical solvents are selected from the group comprising of methanol,
acetone, methylene chloride and purified water.
One skilled in the art would recognize other suitable auxiliary agents, lubricants and
glidants that can be used in the composition of present invention.
Catechol derivatives like entacapone, nitecapone and tolcapone may be administered
with levodopa or carbidopa or benserazide, either separately or in a fixed dose
combination thereof.
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The invention will be further clarified by the following examples, which are intended
to be purely exemplary of the invention and are not intended to limit the scope of the
invention.
GENERAL MANUFACTURING PROCESS
Process A:
1. Sift the drug optionally with suitable excipients through suitable sieve and
granulate with alkalizer solution or mix the drug with alkalizer and optionally
with suitable excipients and granulate with suitable solvents.
2. Dry the wet granules at suitable temperature and size through suitable sieve.
3. Blend the dried granules with lubricant and optionally with diluents. Fill this
blend into capsule or compress the lubricated blend into tablets.
4. Optionally coat the core tablet with coating suspension.
OR
Process B:
1. Sift & Mix the drug with alkalising agent and with atleast one
pharmaceutically acceptable excipient.
2. Lubricate the blend of step 1 with lubricant.
3. Optionally compress the lubricated blend obtained from step 2 or fill into the
capsules.
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OR
Process C:
1. Sift & Mix the drug with alkalising agent and with atleast one pharmaceutically
acceptable excipient.
2. Slug the blend of step 1.
3. Mill and sift the slugs of step 2.
4. Lubricate the blend of step 3 with lubricant.
5. Optionally compress the lubricated blend.
Exarnple-1
Formula:
S. Ingredients mg/tab
No
1. Entacapone 200.00
2. Sodium Hydroxide 19.00
3. Microcrystalline Cellulose 434.40
(Avicel PH 200)
4. Sodium Stearyl Fumarate 6.60
5. Hydroxy propyl methylcellulosie (6 CPS) 13.10
6. Polyethylene Glycol 6000 2.46
7. Titanium Dioxide 0 82
8. Red Iron Oxide 0.13
Manufacturing process:
200mg (29.56%w/w) of Entacapone was sifted through # 60 sieve and granulated
with solution of 19.0mg (2.81%w/w) of Sodium hydroxide in 33.33mg of water. Wet
granules were dried at 60°C and sized through # 60 sieve. Dried granules were
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blended with 434.4 mg (64.21%w/w) of MicrocrystalHne cellulose (Avicel PH 200)
and 6.6mg (0.98%w/w) of Sodium stearyl fumarate. The lubricated blend was
compressed into 660 mg tablets. Thus tablets obtained were coated with coating
suspension containing 13.10mg (1.94%w/w) of Hydroxy propyl methylcellulose
6cps), 2.46mg (0.36%w/w) of Polyethylene Glycol 6000, 0.82mg (0.12%w/w) of
Titanium Dioxide and 0.13mg (0.02%w/w) of Red Iron Oxide .

Example-2
Formula:
S. Ingredients nig/tab %w/w
Nc
I. Entacapone 200.00 29.56
2. Sodium Hydroxide 19.00 2.81
3. Mannitol (Perlitol SD 200) 302.00 44.64
4. Microcrystalline cellulose 129.10 19.08
(Avicel PH 200)
5. Sodium Stearyl Fumarate 9.90 1.46
6. Hydroxy propyl methylcellulose 13.10 1.94
(6 CPS)
7. Polyethylene Glycol 6000 2.46 0.36
8. Titanium Dioxide 0,82 0.12
9. Red Iron Oxide 0.13 0.02
Manufacturing process:
200mg (29.56%w/w) of Entacapone was sifted through # 60 sieve and granulated
with solution of 19,0mg (2.81%w/w) of Sodium hydroxide in 33.33mg of water. Wet
granules were dried at 60°C and sized through # 60 sieve. Dried granules were
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blended with 129.1mg (19.08%w/w) of Microcrystalline cellulose (Avicel PH 200),
302.0mg (44.64%w/w) of Mannitol (Pearlitol SD 200) and 6.6mg (0,98%w/w) of
Sodium stearyl fomarate. The lubricated blend -was compressed into 660 mg tablets.
Thus tablets obtained were coated with coating suspension containing 13.10mg
(1.94%w/w) of Hydroxy propyl methylcellulose (6 CPS), 2.46mg (0.36%w/w) of
Polyethylene glycol 6000, 0.82mg (0.12%w/w) of Titanium Dioxide and 0.13mg
(0.02%w/w)of Red Iron oxide
Example-3
Formula:
S. Ingredients mg/tab
.No
1. Entacapone ~200.00
2. Disodium Hydrogen Phosphate 33.72
3. Microcrystalline Cellulose (Avicel PH 200) 416.3 8
4. Sodium Stearyl Fumarate 9.90
5. Hydroxy propyl Methyl cellulose (6 CPS) 13.10
6. Polyethylene Glycol 6000 ' 2.46
7. Titanium Dioxide 0.82
8. Red Iron Oxide 0.13
Manufacturing process:
200mg (29.56%w/w) of Entacapone was sifted through # 60 sieve and granulated
with solution of 33.72mg (4.98%w/w) of Disodium hydrogen phosphate in lOOmg of
water. Wet granules were dried at 60°C and sized through # 60 sieve. Dried granules
were blended with 416.38 mg (61.55%w/w) of Microcrystalline cellulose (Avicel PH
200) and 9.9mg (1.46%w/w) of Sodium stearyl fumarate. The lubricated blend was
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compressed into 660 mg tablets. Thus tablets obtained were coate4 with coating
suspension containing 13.10mg (1.94%w/w) of Hydroxy propyl rnethylcellulqse
6cps. 2.46mg (0.36%w/w) of Polyethylene glycol 6000, 0.82mg (0.12%w/w) of
Titaniuni dioxide and 0.13mg (0.02%w/w) of Red Iron Oxide ,
Example-4
Formula
S. Ingredients mg/Cap
No
1. Entacapone 200.00
2. Sodium Hydroxide 13.50
3. Mannitol (Perlitol SD 200) 80.50
4. Hydrogenated Castor Oil 6.00
5. Hard Gelatin Capsule (Size 96.00
0)
Manufacturing process:
2QOmg (50.51%w/w) of Entacapone was sifted through # 60 sieve and granulated
with solution of 13,5mg (3.41%w/w) of Sodium hydroxide in 33.33mg of water. Wet
granules were dried at 60°C and sized through # 60 sieve. Dried granules were
blended with 80.5mg (20.31%w/w) of Mannitol (Perlitol SD 200) and 6.0mg
(1.52%W/w) of Hydrogenated castor oil. 300 mg of lubricated blend was filled into
Hard gelatin capsule (Size 0).
Those sKilled in the art will recognize that while specific embodiments have been
illustrate^ and described, various modifications and changes may be made without
departing from the spirit and scope of the invention.
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Other embodiments of the invention will be apparent to those skilled in the from the
consideration of the specification and practice of the invention disclosed herein. It is
also intended that the specification and examples be considered as exemplary only,
with true scope and spirit of the invention being indicated by the following claims.
The references discussed herein are specifically incorporated by reference in their

entirety.
Example: 5
Formula:
S.NO Ingredients mg/Tab
1 Entacapone 200
2 Sodium Hydroxide 19
3 Levodopa 150
4 Garbidopa 37.5
5 Marmitol 105.89
6 PolyvinylpyrroIidone(K30) 6.61
7 Magnesium Stearate 10
8 Hydroxypropyl 13.1
Methy Icel lul ose(6cps)
9 Polyethylene Glycoi 6000 2.46
10 Titanium Dioxide 0.82
11 Red Iron Oxide 0.13
Manufacturing Process:
200 mg (36.7%w/w) of Entacapone is sifted through #60 sieve and granulated with
19 mg(3.5% w/w) of Sodium Hydroxide in 33.33 mg of water. Wet granules are dried
at 60°C and sized through # 60 sieve. 150 mg (27.5%w/w) of Levodopa, 37.5mg{6.9
% w/w) of Carbidopa, 105.89 mg( 19.4%w/w) of Marmitol are sifted through # 40 and
blended. 6.61 mg (1.2%w/w) of Polyvinylpyrrolidone is dissolved in water and
granulated levodopa carbidopa blend. Wet granules are dried at 60°C and sized
through #0;8 mm sieve. Entacapone granules and levodopa carbidopa granules are
blended with 10 mg (1.8%w/w) stearate and blend compressed into tablets of 529 mg
average weight. Thus tablets obtained are coated with coating suspension containing
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13.1(2.4%w/w) of Hydroxypropyl Methylcellulose 6cps, 2.46 mg(0,5%w/w) of
Polyethylene Glycol 6000, 0.82 mg(0,2%w/w) of Titanium Dioxide,
0.13mg(0.02%w/w) of Red Oxide iron.

Example:6
Formula:
S.NO Ingredient mg/Capsulcs

1 Entacapone 200
2 Sodium Hydroxide 19
3 Levodopa 150
4 Carbidopa 37.5
5 Mannitol 104.5
6 PoiyvinylpyrroJidone(K30) 5
7 Magnesium Stearate 6
8 HardGelatin Capsule Size'O' 96
Manufacturing Process:
200 mg (32,4%w/w) of Entacapone is sifted through #60 sieve and granulated with
19 mg (3.1% w/w) of Sodium Hydroxide in 33.33 mg of water. Wet granules are
dried at 60°C and sized through # 60 sieve. 150 mg (24.3%w/w) of Levodopa,
37.5mg (6.1 % w/w) of Carbidopa, 104.5mg(l6-9%w/w) of Mannitol are sifted
through # 40 and blended. 5 mg(0.8 %w/w) of Potyvinylpyrrolidone is dissolved in
water and granulated levodopa carbidopa blend. Wet granules are dried at 60°C and
sized through #0.8 mm sieve. Entacapone granules and levodopa carbidopa granules
are blended with 6 mg (1 %w/w) magnesium stearate and blend filled into Size'O'
capsules of average fill weight 522 mg.
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Example:?
Formula:

S. No Ingredients rag/Cap
1. Nitecapone 200.00
2. Sodium Hydroxide 13,50
3. Mannitol (Perlitol SD 200) 80.50
4. Hydrogenated Castor Oil 6.00
5. Hard Gelatin Capsule (Size 96.00
f 0)
Manufacturing Process:
200mg (50.51%w/w) of Nitecapone is sifted through # 60 sieve and granulated with
solution of 13.5mg (3.41%w/w) of Sodium hydroxide in 33.33mg of water. Wet
granules are dried at 60°C and sized through # 60 sieve. Dried granules are blended
with 80.5mg (20.3l%w/w) of Mannitol (Perlitol SD 200) and 6.0mg (1.52%w/w) of
Hydrogenated castor oil. 300 mg of lubricated blend is filled into Hard gelatin
capsule (Size 0).
Example-8
Dissolution profile of Entacapone Tablets:
Dissolution in pH 5.8 phosphate buffer, basket @ 100 rpm.

Product
Comtan
(Reference;
Entacapone
Tablets 200
(Test) Batch No. Dissolution in %

F0125
Example- 1 15 min
98.63
92.13 30 min 45 min
99.03 99.77
93.82 95.37 60 min
100.23
96.97
-22-

We Claim:
1. A pharmaceutical composition comprising compound having
catechol moiety and one or more alkalising agent optionally with
other active ingredient.
2. A pharmaceutical composition comprising compound having
catechol moiety arid one or more alkalising agent optionally with
other active ingredient, characterised in that the pharmaceutical
composition is free of disintegrant.
3. A pharmaceutical composition according to claim 1 or 2, wherein
compound having catechol moiety is selected from entacapone,
nitecapone or tolcapone.
4. A pharmaceutical composition according to claim 1 or 2, wherein
other active ingredient is carbidopa and / or levodopa.

5. A pharmaceutical composition according to claim 1 or 2, wherein
alkalising agent is selected from the group of sodium hydroxide,
potassium hydroxide, sodium dihydrogen phosphate, disodium
hydrogen phosphate, sodium carbonate, sodium bicarbonate,
potassium hydrogen phosphate, dipotassium hydrogen phosphate,
tripotassium phosphate.


-23-

6. A solid oral dosage form consisting of:
i) a compound having catechol moiety,
ii) alkalising agent(s),
iii) diluent(s),
iv) lubricant(s), and
v) optionally with other active ingredient selected from
carbidopa and/or levodopa.
7. A solid oral dosage form according to claim 6, wherein solid oral
dosage form is tablet or capsule.
8. A solid oral dosage form according to claim 6 consisting of i
i) a compound having catechol moiety,
ii) alkalising agent(s),
iii) diluent(s),
iv) lubricant(s),
v) optionally with other active ingredient selected from
carbidopa and/or levodopa and
characterised in that the solid oral dosage form does not contain
disintegrating agent.
-24-

9. A solid oral dosage form according to claim 6 comprises of:
i) a compound having catechol moiety,
ii) alkalising agent(s),
iii) diluent(s),
iv) lubricant(s),
v) optionally with other active ingredient selected from
carbidopa and/or levodopa and,
characterised in that the solid oral dosage form does not contain
disintegrating agent which is crosslinked cellulose derivative.
10. A solid oral dosage form according to claim 6, wherein the solid
oral dosage form is manufactured by wet granulation or dry
granulation or direct compression.
11. A method for preparing a solid oral dosage form of a tablet or
capsule wherein dosage form comprises a compound having
catechol moiety and alkalising agent, which comprises of
following steps:
a) Sifting of compound optionally with diluents and granulate with
solution of alkalising agent OR Mix the compound with alkalising
agent and optionally with other pharmaceutically acceptable
excipients and granulate with suitable solvent.
b) Drying the wet granules and sizing through suitable screen.
-25-

c) Blending of dried granules with lubricants and optionally with
other pharmaceutically acceptable excipients.
d) Compressing the lubricated blend from step c into tablet OR filling
into capsule.
Dated this on 6th November, 2006

-26-

FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULESV 2003
Complete specification
[See Section 10 and rule 13]

1 Title of the Invention.
"PHARMACEUTICAL COMPOSITION "
2 Applicant (s)
Applicant Name Torrent Pharmaceuticals Ltd.

Nationality Indian

Address Torrent House Off Ashram Road
Near Dinesh Hall
Ahmedabad - 380009. Gujarat
The following specification particularly describes the invention and the
manner in which it is to be performed.


PHARMACEUTICAT, COMPOSITION
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition of practically water
insoluble or low water soluble compounds containing catechol moiety by enhancing
the solubility of such compounds using one or more alkalising agent.
The present invention also relates to a process for preparing such pharmaceutical
composition
BACKGROUND OF THE INVENTION
Low-solubility drugs often show poor bioavailability or irregular absorption, the
degree of irregularity being affected by factors such as dose level, fed state of the
patient, and form of the drug. Increasing the bioavailability of low-solubility drugs
has been the subject of much research. Increasing bioavailability hinges on improving
the concentration of the drug in solution to improve absorption.
It is known that many low-solubility drugs can be formulated so as to increase the
maximum concentration of the drug that will dissolve in an aqueous solution in in-
vitro tests. It has been shown that when such forms are tested in vivo they can
enhance the relative bioavailability of the drug, presumably by enhancing, at least
temporarily, the concentration of dissolved drug present in the gastrointestinal (GI)
tract.
Another approach is that some low-solubility drugs may be formulated in highly
soluble salt forms that provide temporary improvements in the concentration of the
drug in a use environment relative to another salt form of the drug. An example of
-2-

such a drug is sertraline, which in the lactate salt rpm has a higher aqueous solubility
at pH 3 than the HC1 salt form. Use of water Soluble acid addition salt of poorly
soluble drug is disclosed in US Patent 5,441,747.
It is known that other drug form known to provide increased concentrations in
solution of low-solubility drugs consists of drug in a hydrate or solvate crystalline
form of the drug. Such forms often have higher aqueous solubility relative to the
lowest solubility, crystalline form and, therefore, provide higher concentrations of
drug. Polymorphs comprise another drug form that temporarily provides increased
concentrations in solution. Some polymorphs, also referred to herein as "high-energy
crystalline forms," have higher aqueous solubility and therefore can provide enhanced
aqueous concentration of the drug relative to other crystal structures and relative to
the equilibrium concentration.
It is also well known that the amorphous form of a low-solubility drug that is capable
of existing in either the crystalline or amorphous form may also temporarily provide a
greater aqueous concentration of drug relative to the equilibrium concentration of
drug in a use environment. It is believed that the amorphous form of the drug
dissolves more rapidly than the crystalline form, 0ften dissolving faster than the drug
can precipitate from solution. As a result, the amorphous form may temporarily
provide a greater-than equilibrium concentration of drug-
Another method that can temporarily provide a greater than equilibrium drug
concentration is to include a solubilizing agent Such as citric acid, etc. in the drug
form. Such solubilizing agents promote the aqueous solubility of the drug. An
example of the use of a solubilizing agent with a drug to increase aqueous solubility
is the use of solubilizing agents with sertraline. As disclosed in PCT Application No.
99/01120, when sertraline is co dissolved in aqueous solution with a solubilizing
agent, for example, citric acid, the solubility of sertraline is dramatically increased.
-3-

Yet another technique for temporarily achieving a greater than equilibrium
concentration of drug in a use environment is to formulate the drug as an aqueous or
organic solution. For example, drug can be dissolved in polyethylene glycol (PEG) or
an aqueous solution of PEG to which an acid or base may be added or the drug may
be dissolved in an aqueous solution of an acid or base. Alternatively, the drug can be
dissolved in a pharmaceutically acceptable organic liquid such as glycerol, mono-, di-
, or triglycerides, fats or oils.
Another approach to increase the bioavailability of low-solubility drugs has involved
forming amorphous dispersions of drugs with polymers. Examples of attempts to
increase drug concentration by forming a dispersion of the drug with a polymer
include Lahr et a!., U.S. Patent 5,368,864, Kanikanti et al., U.S. Patent 5,707,655 and
Nakamichi et al., U.S. Patent 5,456,923. However, creating an amorphous dispersion
of a drug and polymer(s) does have some drawbacks. For example, some drugs may
degrade at the elevated temperatures used to form some dispersions. Some processes
use organic solvents, which must be thoroughly removed to avoid drug degradation.
Increasing drug solubilization by using combinations of drug and polymer has also
been described. For example, Martin et al., U.S. Patent 4,344,934 mixed poorly-
soluble drugs with polymers such as hydroxypropyl methyl cellulose (HPMC) and
added an aqueous surfactant solution to the drug-polymer mixture. While this results
in improved dissolution, there is only slight enhancement of drug concentration
relative to the equilibrium concentration. Particle size reduction of active principle
may also improve the bioavailabilty.
It is desirable that active pharmaceutical ingredient is released from the oral
composition as soon as possible after ingesting it. This can normally be achieved by
using a solublisation enhancing agent in the pharmaceutical composition. The
solublisation enhancing agent may be a disintegrant, surface active agent or any other
agents that enhance the solublisation. There is vast selection of different solublisation
-4-

enhancing agents, including disintegrants, on the market, which have different
chemical and physical characteristics. When selecting the best solublisation
enhancing agent to be vised in the pharmaceutical composition in combination with

active agent, numerous factors have to be considered., e.g. the chemical and physical
characteristics of the active agents , and solublisation enhancing agent, the chemical
and physical characteristics of the auxiliary agents, such as diluents and binder, the
method of preparing the composition, etc.
Various compound containing catechol moiety like entacapone, nitecapone, tolcapone
or a pharmaceutically acceptable salt thereof, are used as active pharmaceutical
ingredient are practically insoluble in water. Because of this property, dissolution of
the product & bioavailability is always a challenge to develop the product in
formulation.
Entacapone is an inhibitor of catechol-O-methyltransferase (COMT), used in the
treatment of Parkinson's Disease as an adjunct to levodopa / carbidopa therapy.
Formulations of solid medicinal forms with the active ingredient entacapone,
nitecapone or pharmaceutically acceptable salts thereof have already been described
in US6599530. It was found that croscarmellose sodium can be used in an amount of
at least 6% by weight of the composition to resolve the poor dissolution of
entacapone, nitecapone or pharmaceutically acceptable salts thereof. Croscarmellose
sodium is required for satisfactory dissolution as compared to other common
dissolution-improving agents such as sodium lauryl sulphate, sodium starch
glycolate, starch, pregelatinized starch, microcrystalline cellulose or mannitol.
According to this invention, the poor dissolution problem of entacapone can be
resolved by using croscarmellose sodium in an amount of at least 6% by weight of
the composition. This patent justifies use of croscarmellose sodium in the marketed
product.
-5-

Entacapone Tablet is available in US and elsewhere under the ^trade name of
COMTAN®
The inactive ingredients of the COMTAN® Tablet are microcrystalline cellulose,
mannitol, croscarmellose sodium, hydrogenated vegetable oil, hydroxypropyl
methylcellulose, polysorbate 80, glycerol 85%, sucrose, magnesium stearate, yellow
iron oxide, red oxide, and titanium dioxide. Physician's Desk Reference, 59th ed., pp.
2291-2295 (2005)
PRIOR ART
Among the various compounds, entacapone and nitecapone having catechol moiety
are described in U.S. Pat. No. 5,446,194 as catechoI-O-methyltransferase (COMT)
inhibitors. Enteral and parenteral routes of administration are discussed in U.S. Pat.
No. 5,446,194.
Crosslinked cellulose derivative like croscarmeHose sodium enhances the dissolution
of Entacapone in oral compacted dosage form is described in WO 00/15196. The
invention relates to an oral compacted composition comprising entacapone,
nitecapone, or a pharmaceutically acceptable salt thereof, and croscarmeHose sodium
(Ac-Di-Sol) as a dissolution-enhancing agent. It was found that crosslinked cellulose
derivative like croscarmeHose sodium can be used in an amount of at least 6% by
weight of the composition to resolve the poor dissolution of entacapone, nitecapone
or pharmaceutically acceptable salts thereof. According to this invention
croscarmeHose sodium is required for satisfactory dissolution as compared to other
common dissolution improving agents such as sodium lauryl sulphate, sodium starch
glycolate, starch, pregelatinized starch, microcrystalline cellulose or mannitol.
According to this invention, the poor dissolution problem of entacapone can be
-6-

resolved by using croscarmellose sodium in an amount of at least 6% by weight of
the composition.
US20060222703 discloses pharmaceutical compositions of entacapone, levodopa &
carbidopa along with pharmaceutical excipients, wherein the excipients are long
chain polymers having an equilibrium moisture content of atleast 2% and the
preparation methods.
In a research article, titled as "Effect of aqueous solubility and dissolution
characteristics on oral bioavailability of entacapone" (Jouko Savolainen et al. Drug
Development Research 2000; 49 {Issue 4}; pages 238-244) discusses about effect of
hydroxypropyl-β-cyclodextrin (HP-β-CD) on entacapone. This study shows
complexation of entacapone with HP-β-CD (10%w/v) increases the aqueous
solubility of entacapone 12 fold and 85 fold at pH 3,0 and at pH 5,0, respectively.
The present inventors have surprisingly found that pharmaceutical compositions of
the poorly soluble compounds containing catechol moiety such as Entacapone,
nitecapone, tolcapone when formulated along with alkalising agent, and
manufactured by a process such as wet granulation exhibited excellent dissolution
characteristics and were found to be comparable with respect to the marketed
formulation.
It was further surprisingly found that Entacapone could be formulated without using
crosslinked cellulose derivative, or binder or disintegrant without affecting the
dissolution characteristics of the drug.
-7-

OBJECTS OF THE INVENTION
It is an object of the present invention to provide a pharmaceutical composition of
practically water insoluble or low water soluble compounds containing catechol
moiety by enhancing the solubility of such compounds by using one or more
alkalising agent.
Another object of the present invention is to provide a simple granulation process,
like wet granulation for manufacturing of solid oral dosage form for practically water
insoluble or low water soluble compounds containing catechol moiety.
Yet anothei object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, to achieve desired dissolution profile.
Yet another object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, without incorporating crosslinked cellulose derivative, to achieve
desired dissolution profile.
Yet another object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, without incorporating binder, to achieve desired dissolution profile.
Yet another object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, without incorporating disintegrant, to achieve desired dissolution
profile.
-8-

Yet another object of the present invention is to provide pharmaceutical compositions
comprising Catechol derivative as an active ingredient, alkalising agent(s) and one or
more adjuvants, without incorporating crosslinked cellulose derivative, disintegrate
and binder, to achieve desired dissolution profile.
Yet another object of the present invention is to provide pharmaceutical compositions
comprising active ingredient such as catechol derivatives like entacapone, nitecapone
and tolcapone in combination with levodopa, carbidopa or other such compounds.
either separately or in a fixed dose combination thereof.
Further object of the present invention to provide process of preparing pharmaceutical
composition of practically water insoluble or low water soluble compounds
containing catechol moiety.
SUMMARY OF THE INVENTION
Thus according to the first aspect of the present invention there is provided a
pharmaceutical composition and its manufacturing process by solubility enhancement
of practically water insoluble or low water soluble compounds containing catechol
moiety by using one or more alkalising agent.
According to second aspect of the invention the pharmaceutical dosage form is in the
form of a tablet, capsule, powder or pellets or parenteral comprising catechol moiety
and alkalising agent.
Further, the present invention also provides a solid dosage form of compounds
containing catechol moiety, alkalising agent(s), and one or more adjuvants, optionally
without using binder and / or disintegrant and a process for preparation of the same.
-9-

Additional objects and advantages of the invention will be set forth in part in the
description which follows, and in part will be obvious from the description, or may be
learned by practice of invention. The objects and advantages of the invention will be
realized and attained by means of the elements and combinations particularly pointed
out in the appended claims.
It is to be understood that both the foregoing general description and the following
detailed description are exemplary and explanatory only and are not restrictive of the
invention, as claimed.
DETAILED DESCRIPTION OF THE INVENTION
Applicants have found that alkalising agent is effective for increasing the dissolution
rate of practically water insoluble or low water soluble compounds containing
catechol moiety. Present invention relates to a pharmaceutical composition of such
compounds by enhancing the solubility using one or more alkalising agent.'
The present invention also teaches a process for preparing said composition.
An oral dosage form wherein a mixture of an active compound containing catechol
moiety was granulated with alkalising agent(s), then mixed with one or more
auxiliary agent, and further the blends are tableted or enclosed in capsule. The best
dissolution enhancing agent is the one that releases the active ingredient from the
dosage form as fast as possible.
Direct compression may be done by blending active ingredient with alkalising agent
then mixing with one or more auxiliary agents, and further the blends may be tableted
or lubricated blend can be filled in capsule.
-10-

Applicants found that alkalising agent is more efficient in releasing active ingredient
from the oral dosage form than other common dissolution improving agents, such as
sodium lauryl sulphate, polysorbate, starch, mannitol, lactose, pregelatinised starch,
microcrystalline cellulose.
The term "drug" or "active ingredient" refers to an agent, active ingredient compound
or other substance, or compositions and mixture thereof that provide some
pharmacological, often beneficial, effect. Reference to a specific active ingredient
shall include where appropriate the active ingredient and it's pharmaceutically
acceptable salts.
The term "dosage form" denotes any form of the formulation that contains an amount
sufficient to achieve a therapeutic effect.
The term "Practically water insoluble" refers having a solubility of about more than
10,000 parts of solvent required to solubilize one part of drug.
The term "Low water soluble" refers having a solubility of about 30 to 10000 parts of
solvent required to solubilize one part of solute.
Compounds having catechol moiety refers to the active ingredient. Examples of
compounds having catechol moiety comprises of but not limited to entacapone,
nitecapone tolcapone, tretoquinol apomorphine, melevodopa, dobutamine,
dopexamine, droxidopa, fenoldopam, keracyanin, methyldopa, papaveroline and their
pharmaceutically acceptable salts, esters, polymorphs, hydrates, solvates, enantiomers
or mixtures thereof.
-11-

Pharmaceutical Composition
A pharmaceutical dosage form of a tablet or capsule or parenteral which comprises a
pharmaceutically effective amount of active ingredient containing catechol moiety
and alkalising agent.
The present invention also provides a process for preparation of solid dosage form
preferably tablet or capsule of catechol derivative with alkalising agent and one or
more adjuvants.
Pharmaceutical composition according to the present invention is preferably in the
form of a tablet or capsule or parenteral. The active ingredient used in the present
pharmaceutical composition is catechol derivative, which is subjected to alkaline
enviroment, dried and optionally sieved.
The solid dosage form tablet or capsule of the present invention is prepared using
active ingredient and alkalising agent i.e.,.catechol derivative with alkalising agent
and pharmaceutically acceptable excipients selected from the group comprising of
diluents, lubricants, glidants and other phannaceutically acceptable excipients or
adjuvants but without a disintegrant more particularly without a crosslinked cellulose
derivative.
The alkalising agent(s), which are to be used in accordance with the invention, are
now described. It is only required of such alkalising agents to show basicity (pH of
not less than 7) when they are in the form of a 1% aqueous solution or suspension
-12-

Alkalising agent may be selected from the group comprising sodium dihydrogen
phosphate disodium dihydrogen phosphate, trisodium pho'sphate, sodium bicarbonate,
sodium carbonate, sodium hydroxide, potassium hydroxide, potassium hydrogen
phosphate , dipotassium hydrogen phosphate, tripotassium phosphate and other
materials known for such property, "providing alkaline environment" is a process in
which the catechol derivative is mixed with alkalising agent(s). The mixing can be
dry or wet with suitable vehicle, if required. Alkalising agent in the dosage form
ranges from 0.4% to 52.0% by weight.
Diluents may be selected from the group comprising of mannitol, microcrystalline
Cellulose, lactose, starch, dibasic calcium phosphate anhydrous, tribasic calcium
phosphate, kaolin, sucrose, precipitated calcium carbonate, sorbitol, maltodextrin,
powdered cellulose, micro crystalline cellulose and other materials known for such
property. Diluents in the dosage form ranges from 0% to 78.0% by weight.
Lubricants may be selected from the group comprising of stearic acid, sodium stearyl
fumarate, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc
stearate, hydrogenated castor oil, silica, colloidal silica, comstarch, calcium silicate,
magnesium silicate, silicon hydrogel and other materials known for such property.
Lubricants in the dosage form ranges from 0% to 3.0% by weight.
Binders may be selected from the group comprising of polyvinylpyrrolidone,
hydroxypropyl methylcellulose, acacia, alginic acid, hydroxy propyl cellulose,
carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid
glucose, methylcellulose, pregelatinized starch and other materials known to one of
ordinary skill in the art. Binders in the dosage form ranges from 0% to 5.0% by
weight.
-13-

Glidants may be selected from the group comprising of colloidal silicon dioxide,
colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal
silicon, silicon hydrogel and other materials known for such property. Glidants in the
dosage form ranges from 0% to 2.0% by weight.
The pharmaceutical composition may optionally be coated with functional and / or
non-functional layers comprising film-forming polymers, if desired.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl
methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinyl acetate
methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose,
hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate,
cellulose acetate phthalate, cellulose acetate trimellitate; waxes; methacrylic acid
polymers and the like. Alternatively, commercially available coating compositions
comprising film-forming polymers marketed under various trade names, such as
Opadry may also be used for coating. Film-forming polymer in the dosage form
ranges from 1.5% to 4.0% by weight.
Other pharmaceutical solvents are selected from the group comprising of methanol,
acetone, methylene chloride and purified water.
One skilled in the art would recognize other suitable auxiliary agents, lubricants and
glidants that can be used in the composition of present invention.
Catechol derivatives like entacapone, nitecapone and tolcapone may be administered
with levodopa or carbidopa or benserazide, either separately or in a fixed dose
combination thereof.
-14-

The invention will be further clarified by the following examples, which are intended
to be purely exemplary of the invention and are not intended to limit the scope of the
invention.
GENERAL MANUFACTURING PROCESS
Process A:
1. Sift the drug optionally with suitable excipients through suitable sieve and
granulate with alkalizer solution or mix the drug with alkalizer and optionally
with suitable excipients and granulate with suitable solvents.
2. Dry the wet granules at suitable temperature and size through suitable sieve.
3. Blend the dried granules with lubricant and optionally with diluents. Fill this
blend into capsule or compress the lubricated blend into tablets.
4. Optionally coat the core tablet with coating suspension.
OR
Process B:
1. Sift & Mix the drug with alkalising agent and with atleast one
pharmaceutically acceptable excipient.
2. Lubricate the blend of step 1 with lubricant.
3. Optionally compress the lubricated blend obtained from step 2 or fill into the
capsules.
-15-

OR
Process C:
1. Sift & Mix the drug with alkalising agent and with atleast one pharmaceutically
acceptable excipient.
2. Slug the blend of step 1.
3. Mill and sift the slugs of step 2.
4. Lubricate the blend of step 3 with lubricant.
5. Optionally compress the lubricated blend.
Exarnple-1
Formula:
S. Ingredients mg/tab
No
1. Entacapone 200.00
2. Sodium Hydroxide 19.00
3. Microcrystalline Cellulose 434.40
(Avicel PH 200)
4. Sodium Stearyl Fumarate 6.60
5. Hydroxy propyl methylcellulosie (6 CPS) 13.10
6. Polyethylene Glycol 6000 2.46
7. Titanium Dioxide 0 82
8. Red Iron Oxide 0.13
Manufacturing process:
200mg (29.56%w/w) of Entacapone was sifted through # 60 sieve and granulated
with solution of 19.0mg (2.81%w/w) of Sodium hydroxide in 33.33mg of water. Wet
granules were dried at 60°C and sized through # 60 sieve. Dried granules were
-16-

blended with 434.4 mg (64.21%w/w) of MicrocrystalHne cellulose (Avicel PH 200)
and 6.6mg (0.98%w/w) of Sodium stearyl fumarate. The lubricated blend was
compressed into 660 mg tablets. Thus tablets obtained were coated with coating
suspension containing 13.10mg (1.94%w/w) of Hydroxy propyl methylcellulose
6cps), 2.46mg (0.36%w/w) of Polyethylene Glycol 6000, 0.82mg (0.12%w/w) of
Titanium Dioxide and 0.13mg (0.02%w/w) of Red Iron Oxide .

Example-2
Formula:
S. Ingredients nig/tab %w/w
Nc
I. Entacapone 200.00 29.56
2. Sodium Hydroxide 19.00 2.81
3. Mannitol (Perlitol SD 200) 302.00 44.64
4. Microcrystalline cellulose 129.10 19.08
(Avicel PH 200)
5. Sodium Stearyl Fumarate 9.90 1.46
6. Hydroxy propyl methylcellulose 13.10 1.94
(6 CPS)
7. Polyethylene Glycol 6000 2.46 0.36
8. Titanium Dioxide 0,82 0.12
9. Red Iron Oxide 0.13 0.02
Manufacturing process:
200mg (29.56%w/w) of Entacapone was sifted through # 60 sieve and granulated
with solution of 19,0mg (2.81%w/w) of Sodium hydroxide in 33.33mg of water. Wet
granules were dried at 60°C and sized through # 60 sieve. Dried granules were
-17-

blended with 129.1mg (19.08%w/w) of Microcrystalline cellulose (Avicel PH 200),
302.0mg (44.64%w/w) of Mannitol (Pearlitol SD 200) and 6.6mg (0,98%w/w) of
Sodium stearyl fomarate. The lubricated blend -was compressed into 660 mg tablets.
Thus tablets obtained were coated with coating suspension containing 13.10mg
(1.94%w/w) of Hydroxy propyl methylcellulose (6 CPS), 2.46mg (0.36%w/w) of
Polyethylene glycol 6000, 0.82mg (0.12%w/w) of Titanium Dioxide and 0.13mg
(0.02%w/w)of Red Iron oxide
Example-3
Formula:
S. Ingredients mg/tab
.No
1. Entacapone ~200.00
2. Disodium Hydrogen Phosphate 33.72
3. Microcrystalline Cellulose (Avicel PH 200) 416.3 8
4. Sodium Stearyl Fumarate 9.90
5. Hydroxy propyl Methyl cellulose (6 CPS) 13.10
6. Polyethylene Glycol 6000 ' 2.46
7. Titanium Dioxide 0.82
8. Red Iron Oxide 0.13
Manufacturing process:
200mg (29.56%w/w) of Entacapone was sifted through # 60 sieve and granulated
with solution of 33.72mg (4.98%w/w) of Disodium hydrogen phosphate in lOOmg of
water. Wet granules were dried at 60°C and sized through # 60 sieve. Dried granules
were blended with 416.38 mg (61.55%w/w) of Microcrystalline cellulose (Avicel PH
200) and 9.9mg (1.46%w/w) of Sodium stearyl fumarate. The lubricated blend was
-18-

compressed into 660 mg tablets. Thus tablets obtained were coate4 with coating
suspension containing 13.10mg (1.94%w/w) of Hydroxy propyl rnethylcellulqse
6cps. 2.46mg (0.36%w/w) of Polyethylene glycol 6000, 0.82mg (0.12%w/w) of
Titaniuni dioxide and 0.13mg (0.02%w/w) of Red Iron Oxide ,
Example-4
Formula
S. Ingredients mg/Cap
No
1. Entacapone 200.00
2. Sodium Hydroxide 13.50
3. Mannitol (Perlitol SD 200) 80.50
4. Hydrogenated Castor Oil 6.00
5. Hard Gelatin Capsule (Size 96.00
0)
Manufacturing process:
2QOmg (50.51%w/w) of Entacapone was sifted through # 60 sieve and granulated
with solution of 13,5mg (3.41%w/w) of Sodium hydroxide in 33.33mg of water. Wet
granules were dried at 60°C and sized through # 60 sieve. Dried granules were
blended with 80.5mg (20.31%w/w) of Mannitol (Perlitol SD 200) and 6.0mg
(1.52%W/w) of Hydrogenated castor oil. 300 mg of lubricated blend was filled into
Hard gelatin capsule (Size 0).
Those sKilled in the art will recognize that while specific embodiments have been
illustrate^ and described, various modifications and changes may be made without
departing from the spirit and scope of the invention.
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Other embodiments of the invention will be apparent to those skilled in the from the
consideration of the specification and practice of the invention disclosed herein. It is
also intended that the specification and examples be considered as exemplary only,
with true scope and spirit of the invention being indicated by the following claims.
The references discussed herein are specifically incorporated by reference in their

entirety.
Example: 5
Formula:
S.NO Ingredients mg/Tab
1 Entacapone 200
2 Sodium Hydroxide 19
3 Levodopa 150
4 Garbidopa 37.5
5 Marmitol 105.89
6 PolyvinylpyrroIidone(K30) 6.61
7 Magnesium Stearate 10
8 Hydroxypropyl 13.1
Methy Icel lul ose(6cps)
9 Polyethylene Glycoi 6000 2.46
10 Titanium Dioxide 0.82
11 Red Iron Oxide 0.13
Manufacturing Process:
200 mg (36.7%w/w) of Entacapone is sifted through #60 sieve and granulated with
19 mg(3.5% w/w) of Sodium Hydroxide in 33.33 mg of water. Wet granules are dried
at 60°C and sized through # 60 sieve. 150 mg (27.5%w/w) of Levodopa, 37.5mg{6.9
% w/w) of Carbidopa, 105.89 mg( 19.4%w/w) of Marmitol are sifted through # 40 and
blended. 6.61 mg (1.2%w/w) of Polyvinylpyrrolidone is dissolved in water and
granulated levodopa carbidopa blend. Wet granules are dried at 60°C and sized
through #0;8 mm sieve. Entacapone granules and levodopa carbidopa granules are
blended with 10 mg (1.8%w/w) stearate and blend compressed into tablets of 529 mg
average weight. Thus tablets obtained are coated with coating suspension containing
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13.1(2.4%w/w) of Hydroxypropyl Methylcellulose 6cps, 2.46 mg(0,5%w/w) of
Polyethylene Glycol 6000, 0.82 mg(0,2%w/w) of Titanium Dioxide,
0.13mg(0.02%w/w) of Red Oxide iron.

Example:6
Formula:
S.NO Ingredient mg/Capsulcs

1 Entacapone 200
2 Sodium Hydroxide 19
3 Levodopa 150
4 Carbidopa 37.5
5 Mannitol 104.5
6 PoiyvinylpyrroJidone(K30) 5
7 Magnesium Stearate 6
8 HardGelatin Capsule Size'O' 96
Manufacturing Process:
200 mg (32,4%w/w) of Entacapone is sifted through #60 sieve and granulated with
19 mg (3.1% w/w) of Sodium Hydroxide in 33.33 mg of water. Wet granules are
dried at 60°C and sized through # 60 sieve. 150 mg (24.3%w/w) of Levodopa,
37.5mg (6.1 % w/w) of Carbidopa, 104.5mg(l6-9%w/w) of Mannitol are sifted
through # 40 and blended. 5 mg(0.8 %w/w) of Potyvinylpyrrolidone is dissolved in
water and granulated levodopa carbidopa blend. Wet granules are dried at 60°C and
sized through #0.8 mm sieve. Entacapone granules and levodopa carbidopa granules
are blended with 6 mg (1 %w/w) magnesium stearate and blend filled into Size'O'
capsules of average fill weight 522 mg.
-21 -

Example:?
Formula:

S. No Ingredients rag/Cap
1. Nitecapone 200.00
2. Sodium Hydroxide 13,50
3. Mannitol (Perlitol SD 200) 80.50
4. Hydrogenated Castor Oil 6.00
5. Hard Gelatin Capsule (Size 96.00
f 0)
Manufacturing Process:
200mg (50.51%w/w) of Nitecapone is sifted through # 60 sieve and granulated with
solution of 13.5mg (3.41%w/w) of Sodium hydroxide in 33.33mg of water. Wet
granules are dried at 60°C and sized through # 60 sieve. Dried granules are blended
with 80.5mg (20.3l%w/w) of Mannitol (Perlitol SD 200) and 6.0mg (1.52%w/w) of
Hydrogenated castor oil. 300 mg of lubricated blend is filled into Hard gelatin
capsule (Size 0).
Example-8
Dissolution profile of Entacapone Tablets:
Dissolution in pH 5.8 phosphate buffer, basket @ 100 rpm.

Product
Comtan
(Reference;
Entacapone
Tablets 200
(Test) Batch No. Dissolution in %

F0125
Example- 1 15 min
98.63
92.13 30 min 45 min
99.03 99.77
93.82 95.37 60 min
100.23
96.97
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We Claim:
1. A pharmaceutical composition comprising compound having
catechol moiety and one or more alkalising agent optionally with
other active ingredient.
2. A pharmaceutical composition comprising compound having
catechol moiety arid one or more alkalising agent optionally with
other active ingredient, characterised in that the pharmaceutical
composition is free of disintegrant.
3. A pharmaceutical composition according to claim 1 or 2, wherein
compound having catechol moiety is selected from entacapone,
nitecapone or tolcapone.
4. A pharmaceutical composition according to claim 1 or 2, wherein
other active ingredient is carbidopa and / or levodopa.

5. A pharmaceutical composition according to claim 1 or 2, wherein
alkalising agent is selected from the group of sodium hydroxide,
potassium hydroxide, sodium dihydrogen phosphate, disodium
hydrogen phosphate, sodium carbonate, sodium bicarbonate,
potassium hydrogen phosphate, dipotassium hydrogen phosphate,
tripotassium phosphate.


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6. A solid oral dosage form consisting of:
i) a compound having catechol moiety,
ii) alkalising agent(s),
iii) diluent(s),
iv) lubricant(s), and
v) optionally with other active ingredient selected from
carbidopa and/or levodopa.
7. A solid oral dosage form according to claim 6, wherein solid oral
dosage form is tablet or capsule.
8. A solid oral dosage form according to claim 6 consisting of i
i) a compound having catechol moiety,
ii) alkalising agent(s),
iii) diluent(s),
iv) lubricant(s),
v) optionally with other active ingredient selected from
carbidopa and/or levodopa and
characterised in that the solid oral dosage form does not contain
disintegrating agent.
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9. A solid oral dosage form according to claim 6 comprises of:
i) a compound having catechol moiety,
ii) alkalising agent(s),
iii) diluent(s),
iv) lubricant(s),
v) optionally with other active ingredient selected from
carbidopa and/or levodopa and,
characterised in that the solid oral dosage form does not contain
disintegrating agent which is crosslinked cellulose derivative.
10. A solid oral dosage form according to claim 6, wherein the solid
oral dosage form is manufactured by wet granulation or dry
granulation or direct compression.
11. A method for preparing a solid oral dosage form of a tablet or
capsule wherein dosage form comprises a compound having
catechol moiety and alkalising agent, which comprises of
following steps:
a) Sifting of compound optionally with diluents and granulate with
solution of alkalising agent OR Mix the compound with alkalising
agent and optionally with other pharmaceutically acceptable
excipients and granulate with suitable solvent.
b) Drying the wet granules and sizing through suitable screen.
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c) Blending of dried granules with lubricants and optionally with
other pharmaceutically acceptable excipients.
d) Compressing the lubricated blend from step c into tablet OR filling
into capsule.
Dated this on 6th November, 2006

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