FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "Extended Release Formulations of Donepezil Hydrochloride"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The invention relates to an oral extended release solid pharmaceutical composition of therapeutically effective amount of donepezil or pharmaceutically acceptable sait thereof, comprising at least one pH independent polymeric release retardant and at least one more pharmaceutically acceptable excipient. The invention further describes a process for preparation of donepezil hydrochloride extended release tablet formulation which is suitable for scale up and commercial level manufacturing. Donepezil formulation of the present invention exhibits extended drug release profile over the period of 12 hours. BACKGROUND OF THE INVENTION
Donepezil which is chemically (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[l -(phenyl methyl)-4-piperidinyl]methyl]-lH-inden-l-one) is a known reversible inhibitor of acetyl cholinesterase. Donepezil and its salts, have application in the treatment of a variety of disorders, including dementia and attention deficit disorder. In particular, donepezil hydrochloride is employed as a pharmaceutically active agent for the symptomatic treatment of mild to moderate Alzheimer's dementia and is currently formulated as film-coated tablets as well as orally disintegrating tablet formulation of 5 milligram (mg) and 10 mg doses for once a day oral administration under the trade name ARJCEPT and ARICEPT ODT respectively.
The immediate release formulations of donepezil result in a spike in the patient's blood plasma levels within 2 to 5 hours after administration of the drug. Such high

drug levels exert side effects, such as nausea, vomiting, and headaches which are more prevalent at initial high doses of acetylcholinesterase inhibitors, resulting in a reduction of patient compliance.
Further the conditions such as moderate to severe Alzhiemer's dementia need still higher doses which may range from 10 to 25 mg of donepezil. If higher strength donepezil formulations are designed as immediate release formulations for such patients, then it would be desirable to provide sufficient therapeutic amounts of donepezil to the patient; at the same time reducing cholinergic adverse events to get desirable benefit out of the treatment.
The prior art is directed towards provisions of several modified release dosage forms for donepezil.
US Patent Application US20060280789 describes matrix type sustained release formulation of donepezil comprising at least one enteric polymer along with water-insoluble polymer. Use of enteric polymer such as methacylic acid copolymer controls the release of basic drug in acidic environment of stomach and releases the drug in neutral to alkaline medium. Such matrix system containing pH dependent polymer may result in unpredictable or burst release of drug once it reaches alkaline medium of upper intestine.
Another US Patent Application US20050232990 relates to number of donepezil formulations such as immediate release formulations, controlled release formulations in the form of multiparticulates as well as taste masked or sprinkle formulations

using different polymer systems so as to achieve drug release at variable sites in GIT. However the application does not describe the composition, process of preparation or drug release of any specific extended release formulation to enable a person skilled in the art to produce such formulations for relevant applications. Accordingly, there is a continuous need for an alternate extended release higher strength donepezil composition with reduced side effects arising due to immediate release of the drug from formulation.
After rigorous experimentation it has been found by inventors of the present invention that donepezil extended release formulation of higher strength (23 mg) designed using pH independent polymeric release retardants exhibits specific controlled drug release over entire gastrointestinal tract desirable for treatment of moderate to severe dementia. Use of pH independent polymers in this invention avoids incomplete drug release or burst release in lower GIT; which is advantageous over use of pH dependent or enteric polymer as used in marketed formulation. Donepezil formulation of present invention is comprised of pH independent hydrophilic or hydrophobic polymeric release retardant or the mixture thereof and at least one more pharmaceutically acceptable excipient. The formulation is a matrix formulation which may be prepared by direct compression or wet granulation. Thus the formulation of the invention is simple to formulate using conventional tableting equipments. The formulation exhibits pH independent controlled release profile which is advantageous and still comparable with existing marketed formulations.

SUMMARY OF THE INVENTION
The present invention provides an extended release solid pharmaceutical composition comprising:
a) a therapeutically effective amount of donepezil or pharmaceutically acceptable salt thereof;
b) at least one pH independent polymeric release retardant and,
c) at least one more pharmaceutically acceptable excipient,
The invention further relates to method of preparation for donepezil formulation that
exhibits extended drug release profile over extended time period which is
comparable with Innovator's formulation.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have addressed the need of developing an extended release
dosage form for higher strength of donepezil (23 mg) providing desired drug release
profile, thus avoiding incomplete drug release or burst release in lower GIT
occurring because of use of pH independent polymeric release retardant in donepezil
formulation.
A "therapeutically effective amount" means the amount of a compound that, when
administered to a mammal for treating a state, disorder or condition is sufficient to
effect a treatment. The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, physical condition and
responsiveness of the mammal to be treated.

The term "release retardant" as used here means a pharmaceutically acceptable excipient that can retard or slow down the release of an active pharmaceutical ingredient from the formulation.
The term "hydrophilic polymer" as used here includes a pharmaceutically acceptable polymeric excipient that has affinity for water, and becomes soluble or swells after it gets into contact with physiological fluid or aqueous medium. The hydrophilic polymer is selected from the group comprising of cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylpropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose; polymers of acrylic acids such as carbopol derivatives; natural polymers like pectin, guar gum, inulin, xanthan gum, locust bean gum, sodium alginate; other hydrophilic polymers such as polyethylene glycol, polyethylene oxide, and the like; or the combination thereof. The term "hydrophobic polymer" as used here includes a pharmaceutically acceptable polymeric excipient that is insoluble in water or in an aqueous buffer solution at a pH anywhere in the range of 1.0 to 8.0. Such polymer does not even swells after it gets into contact with physiological fluid or aqueous medium. Exemplary hydrophobic polymers include cellulose ethers (cellulose alkyl ethers, including cellulose Cl-6 alkyl ethers, such as methylcellulose, ethylcellulose, propylcellulose, ethylmethylcellulose, ethylpropylcellulose, isopropylcellulose, butylcellulose and the like; cellulose aralkyl ethers such as benzyl cellulose and the

like; cellulose cyanoalkyl ethers such as cyanoethyl cellulose, cyanomethyl cellulose, cyanoethylmethyl cellulose, cyanopropyl cellulose, and the like), cellulose esters (cellulose organic acid esters such as cellulose acetate butyrate, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate propionate and the like), methacrylic acid-acrylic acid copolymers (e.g., EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, Rohm GmbH, Germany) and the like. Of these polymers, cellulose C1-6 alkyl ethers, aminoalkyl methacrylate copolymers (e.g., EUDRAGIT® RL, EUDRAGIT® RS, Rohm GmbH, Germany) and ethyl acrylate-methyl methacrylate copolymers (e.g., EUDRAGIT® NE, Rohm GmbH, Germany) are preferred. In one embodiment, ethylcellulose (ETHOCEL®, Dow Chemical) is preferred.
The amount of hydrophilic polymer in the extended release formulations is not particularly limited, but may be from 5 to 80% by weight; from 8 to 70% by weight; from 10 to 60% by weight; or from 15 to 50% by weight, based on 100% by weight of the matrix type sustained release formulation.
The amount of hydrophobic polymer in donepezil extended release formulations is not particularly limited, but may be from 1 to 90% by weight; from 5 to 70% by weight; from 10 to 50% by weight; based on 100% by weight of the extended release formulation.
"Reduced initial burst release" as per this invention means the reduction in release of active ingredient from the dosage form at initial time points.

Extended release of the active agent from the formulation of present invention is
achieved by use of at least one pH independent polymer.
In one of the embodiment of this invention, the composition employs a mixture of
pH independent polymeric release retardants.
In one more embodiment of the present invention the composition is comprised of
combination of two pH independent hydrophilic polymers such as cellulose polymer
like hydroxypropyl methyl cellulose and natural gum like xanthan gum or the like.
In still one more embodiment of the present invention, the composition makes use of
combination of hydrophilic and hydrophobic polymer such as xanthan gum and ethyl
cellulose or the like.
Use of suitable hydrophilic polymer in sufficient quantity helps to hydrate the
surface of formulation quickly when it comes in contact with gastrointestinal fluid
and forms a gel layer. The hydrophilic polymer swells during its GIT transit and
forms a gelling matrix which avoids erosion of the dosage form. Drug diffuses out of
the swollen matrix over the period of 12 to 14 hours. The composition where the
combination of hydrophilic and hydrophobic polymer is employed, drug is dispersed
in the matrix of this combination polymers. Hydrophilic polymer will swell and at
the same time hydrophobic polymer will form non eroding film around drug
particles, thus further minimizing the drug release.
Proper choice and combination of pH independent polymeric release retardant results
into a matrix system that swells after contact with gastrointestinal fluid and by virtue

of this also maintains the size of the dosage form thus avoiding inconsistent drug
release rates arising from variable transit times of the dosage form through the
gastrointestinal tract.
Compositions of the present invention will generally contain at least one
pharmaceutically acceptable carrier conventionally used in the art of tablet and/or
capsule formulation.
Pharmaceutical excipients are routinely incorporated into solid dosage forms to ease
the manufacturing process as well as to improve the performance of the dosage form.
These can include diluents, lubricants, granulating aids, anti-adherents, gildants and
the like; or combinations thereof.
The present invention may include one or more fillers or excipients in an amount
within the range of from about 0 to about 90% by weight and preferably from about
1 to about 80% by weight such as lactose, corn starch, modified corn starch,
mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose
derivatives such as wood cellulose and microcrystalline cellulose.
The binders are selected from the group, comprising of starch, polyethylene glycol,
polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polymethacrylic acid
derivatives, ethyl cellulose, cross-linked carboxymethylcellulose, low viscosity
hydroxypropyl methyl cellulose and hydroxypropylcellulose and natural and
synthetic gums. Binders may be incorporated into the system at a concentration of
about 0.5-20% by weight, preferably 1-10% and more preferably 2-7.5% by weight.

The formulation may include one or more lubricants in an amount within the range of from about 0,2 to about 8% and preferably from about 0.5 to about 2% by weight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and the like and mixtures thereof. Other conventional pharmaceutical ingredients, which may optionally be present, include preservatives, stabilizers, FD & C colors and the like; or combinations thereof.
The invention relates to an oral extended release solid pharmaceutical composition of Donepezil comprising pH independent polymeric release retardant and at least one pharmaceutically acceptable excipient. The invention further relates to process for preparation of donepezil extended release tablet formulation which is suitable for scale up and commercial level manufacturing.
The process of preparation is comprised of mixing drug with pH independent polymeric excipient and at least one more pharmaceutically acceptable excipient. Drug and excipients are blended well and then subjected to either wet granulation or direct compression to get the tablets. These tablets are then film coated using low viscosity polymer to get non functional coat for aesthetic purpose. The drug release study from such formulation is carried out using USP dissolution apparatus I in pH 4.5 , 6.8 buffer as well as 0.1 N HC1 using 900 ml volume of dissolution media at 100 rpm.

Tablets formulated according to the invention allow for extended release of donepezil over at least a twelve-hour period following oral administration, the in vitro release rate preferably corresponds to the following % rate of active agent released as shown in following Table:

Time (hr) % Released in pH6.8 % Released in pH4.5 % Released in 0.1 N HC1
1 5-30 5-35 5-35
2 30-50 35-55 35-60
4 50-65 55-75 60-80
12 65-100 75-100 85-100
An extended release preparation according to the present invention is one that
achieves slow release of a drug over an extended period of time, thereby extending
the duration of drug action over that achieved by conventional delivery. Preferably,
such a preparation maintains a drug concentration in the blood within the therapeutic
range for 12 hours or more.
Donepezil extended release formulation of the present invention exhibits
comparative dissolution profile with innovator formulation, when tested under
similar conditions.
The formulation is also stable at specific storage conditions for its drug assay,
dissolution parameter and related substances.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and
are intended to be included within the scope of the present invention.

EXAMPLES Example I

Sr.No. Ingredients Mg/tab
1. Donepezil Hydrochloride 23
2. Lactose monohydrate 117.5
3. Ethylcellulose 44
4. Xanthan gum 7.5
5. Hydroxypropylcellulose (HPC-L) 6
6. Magnesium stearate 2
Total weight of Tablet 200
Procedure:
Lactose monohydrate, ethylcellulose, xanthan gum and L- hydroxy propylcellulose were sifted through 40 mesh. Donepezil hydrochloride was mixed with the excipients in low shear blender for 30 min. The blend was lubricated using magnesium stearate for 5 minutes in low shear blender at slow speed. The blend was compressed with appropriate tooling by using single rotary compression machine. Example II:

Sr.No. Ingredients Mg/tab
1. Donepezil Hydrochloride 23
2. Lactose monohydrate 119
3. Hydroxypropyl methylcellulose (HPMC K4M) 40
4. Xanthan gum 10
5. Hydroxypropyl cellulose (HPC-L) 6
6. Magnesium stearate 2
Total weight of Tablets 200

Procedure:
Lactose monohydrate, hydroxypropyl methyl cellulose, xanthan gum and L- hydroxy
propylcellulose were sifted through 40 mesh. Donepezil hydrochloride was mixed
with the excipients in low shear blender for 30 min. The blend was lubricated using
magnesium stearate for 5 minutes in low shear blender at slow speed.
The blend was compressed with appropriate tooling by using single rotary
compression machine.
Example I and II tablets were film coated using following composition using
Autocoater;

Sr.No Ingredients Mg/tab
1 Hydroxypropylmethyl cellulose
(HPMC E5) 6
2 Polyethylene glycol (PEG 6000) 1.2
3 Purified Talc 0.2
4 Titanium dioxide 0.6
5 Purified water qs
Weight buildup 8
Final weight of coated tablets 208
Dissolution study of the formulation:
Drug release profile of Example II formulation was studied in three dissolution media, 0.1 N HC1, pH 4.5 buffer and pH 6.8 buffer, volume 900 ml using basket at 100 rpm. Innovator's donepezil formulation 23 mg was studied for in vitro drug release at similar dissolution conditions. The study was carried using both the formulations at the same time and drug release profile was monitored to get comparative dissolution profile.

Table No. 1 Drug release study from Example II and Innovator's formulation

B.No. Formulation Example II Innovator's (Eisai) Donepezil 23 mg formulation
Dissolution pH6.8 pH4.5 0.1N HC1 pH6.8 pH4.5 0.1N HC1

900ml, basket, l00rpm

Mean Mean Mean Mean Mean Mean
1 28 34 33 26 41 33
2 35 49 48 34 55 47
4 58 77 75 51 78 67
6 16 92 89 69 87 82
8 85 100 98 83 92 89
12 95 100 96 101 98 94
14 99 102 103 101 99 98
Table No. 1 shows drug release profile from the donepezil extended release formulation of the present invention and Innovator's formulation at above said conditions. It can be seen that the formulation of the present invention which employs mixture of pH independent polymers in its composition, exhibits comparative dissolution profile with Innovator's formulation. Stability Study:
Stability study of the extended release donepezil formulation (23 mg) of the present invention was carried out at 40°C/75% RH, stored in HDPE Containers for 3 months. The stability was evaluated for the parameters like assay, dissolution and related substances is shown in table no. 2

TabJe No. 2 Stability study data for donepezil formulation Example II

S.No. Parameter Initial 40°C/75% RH

3 months
1. Assay (%) 97.8 100.4
2. Dissolution (hr)
(900 ml, 6.8 Phosphate buffer, USP Type 1,100 rpm)
1
4 12 21 59 103 20 59 100
3. Related substances
DNP1 (Debenzyl impurity) 0.02 0.01

Benzylidine impurity 0.01 0.01

N-Oxide impurity ND ND

Any unknown impurity 0.01 0.01
Total impurities 0.04 0.03
ND: Not Detected
It is found that the extended release formulation of the present invention is stable
with respect to studied parameters at given storage conditions for 3 months period.

We Claim,
1. An extended release solid pharmaceutical composition comprising:
a) a therapeutically effective amount of donepezil or pharmaceutically acceptable salt thereof;
b) at least one pH independent polymeric release retardant and,
c) at least one more pharmaceutically acceptable excipient,
wherein the formulation exhibits extended drug release profile over period of 12 hours.
2. An extended release donepezil composition of claim 1, wherein a pH independent polymeric release retardant is selected from hydrophilic polymer, hydrophobic polymer or mixture thereof.
3. An extended release donepezil composition of claim 1, wherein pH independent polymeric release retardant is selected from hydrophilic polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylpropyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyethylene oxide; locust bean gum, pectin, guar gum, inulin, xanthan gum, sodium alginate and the like or mixtures thereof.
4. An extended release donepezil composition of claim 3, wherein hydrophilic pH independent polymeric release retardant is selected from hydroxypropyl methyl cellulose, xanthan gum or mixture thereof.

5. An extended release donepezil composition of claim 2, wherein pH independent polymeric release retardant is selected from hydrophobic polymers such as ethyl cellulose, propyl cellulose, ethylmethyl cellulose, ethylpropyl cellulose, isopropyl cellulose, cyanoethyl cellulose, cyanomethyl cellulose, cellulose acetate butyrate, cellulose propionate; and the like or mixtures thereof.
6. An extended release donepezil composition of claim 5, wherein hydrophobic pH independent polymeric release retardant is ethyl cellulose,
7. An extended release donepezil composition of claim 1, wherein at least one more pharmaceutically acceptable excipient is selected from the group of diluent, binder, filler, glidant, lubricant, film forming agent, plasticizer and the like.
8. An oral extended release formulation comprising of donepezil hydrochloride, having an in vitro drug release profile comparable to Innovator's formulation (as determined by USP type I apparatus using volume 900 ml, pH 6.8 phosphate buffer at 37°C and 100 rpm with following details:
5 to 30% released in 1 hour 30 to 50% released in 2 hours, 50 to 65% released in 4 hours 65 to 100% released over 12 hours.
9. A process for preparing extended release donepezil formulation, comprising

(a) physically mixing donepezil with at least one pH independent release retarding polymer and at least one more pharmaceutically acceptable excipient such as diluent, binder and the like.
(b) blending the physical mix of step (a) to get a uniform powder mix and lubricating the blend;
(c) compressing the powder blend of step (b) into tablet composition
(d) coating the tablet formulation using non functional coating polymer.
10. An oral extended release donepezil solid formulation as described in the example.