FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - MODIFIED RELEASE FORMULATIONS OF DONEPEZIL
2. Applicant(s)
(a) NAME: ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(C) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

MODIFIED RELEASE FORMULATIONS OF DONEPEZIL
FIELD OF INVENTION
The present invention relates to modified release formulations of Donepezil.
BACKGROUND OF THE INVENTION
Donepezil HC1 (Donepezil Hydrochloride) is a reversible inhibitor of the enzyme
acetylcholinesterase.
Following are the approved formulations of Donepezil in the USA market:-
1. ARICEPT® 5 mg and 10 mg film-coated tablets containing Donepezil HC1 along with lactose monohydrate, cornstarch, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate. The film coating contains talc, polyethylene glycol, hypromellose, and titanium dioxide. Additionally, the 10 mg tablet contains yellow iron oxide (synthetic) as a coloring agent.
2. ARICEPT® ODT 5 mg and 10 mg tablets containing Donepezil HCI along with carrageenan, mannitol, colloidal silicon dioxide, and polyvinyl alcohol. The 10 mg tablet contains yellow iron oxide (synthetic) as a coloring agent.
3. ARICEPT® 23 mg film-coated tablets containing Donepezil HC1 along with ethylcellulose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and methacrylic acid copolymer, Type C. The reddish color film coating includes ferric oxide, hypromellose 2910, polyethylene glycol 8000, talc and titanium dioxide.
ARICEPT® is indicated for the treatment of dementia of the Alzheimer's type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer's Disease (AD). "Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. Farlow MR, Salloway S, Tariot PN, Yardley J, Moline ML, Wang Q, Brand-Schieber E, Zou H, Hsu T, Satlin A; Clin

Ther. 2010 Jul;32 (7): 1234-51 states that; in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d.
The US2006/0280789 Al patent application exemplifies the means to deliver the high dosage of donepezil in a sustained release manner by the manufacture of matrix drug delivery systems with a water-insoluble polymer and an enteric polymer as the essential components. Also exemplified are the wax matrices, multiparticulates such as sustained release granules, ion-exchange resin containing dosage forms and pulsed release dosage forms.
The present invention contributes to provide modified drug delivery dosage forms of Donepezil HC1 with the following embodiments. -
a) Immediate release core containing Donepezil with an osmotic agent coated with at least one water-insoluble polymer, at least one enteric polymer and optional film coat;
b) Hydrophilic matrix containing Donepezil coated with water-insoluble polymer;
c) Enteric polymer matrix containing Donepezil;
d) Uncoated water-insoluble polymer and water-soluble resin matrix containing
Donepezil;
e) Immediate release core containing Donepezil with an osmotic agent coated with at least one water-insoluble polymer, at least one enteric polymer and immediate release film coat containing Donepezil and
f) Hydrophilic matrix containing Donepezil with allyl ethers of pentaerythritol, water insoluble filler and optionally a water soluble polymer.

SUMMARY OF THE INVENTION
The present invention relates to modified release formulations of Donepezil.
In another aspect, the invention relates to a modified release formulation of
Donepezil comprising: (A) an immediate release core comprising Donepezil with an
osmotic agent; (B) a coating comprising at least one water-insoluble polymer and at
least one enteric polymer and optionally (C) a film coat comprising at least one
polymer.
In another aspect, the invention relates to a modified release formulation of Donepezil comprising: (A) an immediate release core comprising Donepezil with an osmotic agent; (B) a coating comprising at least one water-insoluble polymer and at least one enteric polymer and (C) an immediate release film coating comprising Donepezil and at least one polymer.
In another aspect, the invention relates to a modified release formulation of Donepezil in the form of a coated hydrophilic matrix comprising Donepezil, at least one water soluble polymer and at least one water-insoluble polymer.
In another aspect, the invention relates to a modified release formulation of Donepezil in the form of a matrix comprising Donepezil and at least one enteric polymer.
In another aspect, the invention relates to a modified release formulation of Donepezil in the form of an uncoated matrix comprising Donepezil, at least one water-insoluble polymer and at least one water-soluble resin.

In another aspect, the invention relates to a modified release formulation of Donepezil in the form of a hydrophilic matrix comprising Donepezil, allyl ethers of pentaerythritol, at least one water-insoluble filler and optionally at least one water soluble polymer.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to modified release formulations of Donepezil.
The term "Donepezil" as used herein includes donepezil base and salts of the donepezil base, unless otherwise indicated.
In another aspect, the invention relates to a modified release formulation of Donepezil comprising: (A) an immediate release core comprising Donepezil with an osmotic agent; (B) a coating comprising at least one water-insoluble polymer and at least one enteric polymer and optionally (C) a film coat comprising at least one polymer.
The modified release formulation of Donepezil comprises at least one water-insoluble polymer selected from cellulose ethers, cellulose esters, methacrylic acid-acrylic acid copolymers and the like. More specifically, ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups and the like. Suitable release controlling amount of water-insoluble polymer may be from 1 to 50% w/w or 1-15% w/w or 1-10% w/w or 1-5% w/w of the total weight of the formulation. The water-insoluble polymer applied as a membrane in this case has the role to control the diffusion of donepezil in the surrounding medium. For example, ethylceilulose with an ethoxyl content of 48-

49.5% can be used in the form of a solution having the viscosity in the range of 5-110 mPa-s or 6-8 mPa-s or 9-11 mPa-s for a 5% solution in toluene: ethanol (80:20) at 25°C or 45-55 mPa-s for a 5% solution in toluene ethanol (60:40) at 25°C. Any desired range of viscosity can be obtained by mixing different grades of ethylcellulose. The solvents for the solution include but are not limited to chlorinated aliphatic hydrocarbons such as dichloromethane, alcohols such as isopropanol or mixtures thereof. The control of diffusion can be significantly modulated. For example, the control of diffusion of an ethylcellulose membrane can be significantly modulated by inclusion of hydroxypropylmethylcellulose in the membrane. Plasticizers can be included in the water-insoluble polymer membrane to provide a desired flexibility to the membrane in an amount of about 5-30% by weight of total solids in the solution. As an example, fatty acid esters, triethyl citrate, propylene glycol, polyethylene glycols such as polyethylene glycol 1500 and the like can be used as plasticizers. The amount of plasticizer may be 0-10% or 0-5% or 0-2% by weight of the formulation and usually depends on the amount of the polymer used. For example, in case of ethylcellulose film the amount of plasticizer would be about one-half the polymer total of the coating solution. The coating solution may additionally contain water soluble substances such as polyvinylpyrrolidone and the like.
Suitable osmotic agents to be used in the immediate release core with donepezil include, but are not limited to polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, lactose, sucrose, fructose, mannitol, sodium chloride, potassium chloride, fumaric acid, succinic acid, lactic acid, tartaric acid and the like and mixtures thereof. The osmotic agents are water soluble and perform the role of facilitating the diffusion of Donepezil from the dosage form. Depending on the dosage form, the osmotic agent/s

can be used in an amount upto about 90% w/w or upto about 70% w/w or upto about 60% w/w of the dosage form.
The modified release dosage forms are coated with one or more enteric polymers. Examples of enteric polymers include, but are not limited to, suitable polymethacrylates (such as for example Eudragit® L, Eudragit® S and the like), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, suitable poly(methylvinyl ether/maleic anhydride) copolymers and derivatives, ethyl methacrylate-methylmethacrylate-chlorotrimethylammonium ethyl methacrylate copolymer, natural resins such as zein, shellac and the like and commercially available enteric dispersion systems, including for example aqueous dispersions of methacrylic acid-ethyl acrylate copolymers ( such as Eastacryl 30 D, Kollicoat MAE 30 D, Kollicoat MAE 30 DP and the like) and combinations of such polymers or materials. The choice of suitable enteric polymer depends on the pH at which the Donepezil release is desired. For example, in case of Eudragit® L 100-55 [Poly (methacrylic acid-co-ethyl acrylate) 1:1] the Donepezil release is targeted at a pH of 6-7.The enteric polymer/s are applied as a coat over the water-insoluble polymer membrane. The coating solution for this purpose contains "in addition to the enteric polymer/s a plasticizer which is described above. The enteric polymer may be present in a suitable amount to control the release of donepezil. For example, Eudragit® L 100-55

can be present in an amount of upto about 10% w/w or 7% w/w or 5% w/w of the formulation.
An optional film coating can be applied using the materials and methods known to the person skilled in the art. Examples of film coating material includes Opadry which is Colorcon's customized, one-step film coating system which combines polymer, plasticizer and pigment, as required, in a dry concentrate. For example, Opadry® white YS-1-7040 contains hypromellose (hydroxypropylmethylcellulose), polyethylene glycol, talc and titanium dioxide. The film coating can be applied in an amount upto about 5% w/w of the formulation.
In another aspect, the invention relates to a modified release formulation of Donepezil comprising: (A) an immediate release core comprising Donepezil with an osmotic agent; (B) a coating comprising at least one water-insoluble polymer and at least one enteric polymer and (C) an immediate release film coating comprising Donepezil and at least one polymer.
This alternative embodiment of the above described embodiment includes donepezil in the film coating which achieves the objective of providing an immediate release of the donepezil in the film coating followed by sustained release of donepezil from the immediate release core which is modulated by the water insoluble polymer and the enteric polymer, as described above.
The immediate release core containing Donepezil with an osmotic agent can be prepared by direct compression, wet granulation, dry granulation such as roller compaction and slugging using equipments well-known to a person skilled in the art and also Remington's Pharmaceutical Sciences, 18th edition, 1990, Mack publishing Company Easton, Pennysylvania 18042 (and even the recent editions) describe such

processes for the preparation of solid dosage forms. For example, the granules can be made from Donepezil, osmotic agent and binder with optional filler. Thereafter, the granules can be compressed into tablets after lubrication; which will subsequently be coated with coats containing water-insoluble polymer, enteric polymer and film coating which contains or does not containing donepezil.
In another aspect, the invention relates to a modified release formulation of Donepezil in the form of a coated hydrophilic matrix comprising Donepezii, at least one water soluble polymer and at least one water-insoluble polymer.
A hydrophilic matrix, controlled-release system is a dynamic one involving polymer wetting, polymer hydration, gel formation, swelling, and polymer dissolution. At the same time, other soluble excipients or donepezil will also wet, dissolve, and diffuse out of the matrix while insoluble materials will be held in place until the surrounding polymer/excipient/Donepezil complex erodes or dissolves away.
The mechanism by which donepezil release is controlled in the matrix is dependent on many variables. The main principle is that the water-soluble polymer, present throughout the matrix hydrates on the outer surface of the matrix to form a gel layer. Throughout the life of the matrix, the rate of Donepezil release is determined by diffusion through the gel and by the rate of tablet erosion. A fast rate of hydration followed by quick gelation and polymer/polymer coalescing is necessary for a rate-controlling polymer to form a protective gelatinous layer around the matrix. This prevents the tablet from immediately disintegrating, resulting in premature Donepezil release. An example of such a matrix is a hydrophilic matrix containing hydroxypropylmethylcellulose K100MCR and hydroxypropylmethylcellulose K15M.

The hydrophilic matrix containing donepezil contains water soluble materials such as hydroxyalkylcellulose. The hydroxyalkylcellulose is preferably a hydroxy (C.sub.l to C.sub.6) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, hydroxyethyl cellulose. The amount of hydroxyalkyl cellulose in the formulation will be determined by the rate of donepezil release required. The suitable amount of hydroxyalkyl cellulose may be from about 1-90% w/w or 1% - 50% w/w or 5% - 30% w/w of the total weight of the formulation. Also, the type of hydroxyalkyl cellulose in the formulation will be determined by the rate of donepezil release required. For example, the hydration rates of the various grades of hydroxypropylmethylcellulose products differ because of varying proportions of two chemical substituents viz. hydroxypropoxyl and methoxyl substitution, attached to the cellulose backbone. The hydroxypropoxyl substitution is relatively hydrophilic in nature and greatly contributes to the rate of hydration of hydroxypropylmethylcellulose. The methoxyl substitution is relatively hydrophobic in nature and does not contribute significantly to the rate of hydration of hydroxypropylmethylcellulose. Substitution has a very significant impact on the performance of hydroxypropylmethylcellulose in hydrophilic matrix systems. Thermal gelation is a useful way to examine how substitution affects polymer properties. The hydroxypropylmethylcelluloses with approximate gel points in 2% aqueous solution of 70°C usually establish the gel barrier the quickest because, they have the highest ratio of hydroxypropoxyl to methoxyl substitution. The example of such hydroxypropylmethylcelluloses includes hydroxypropylmethylcellulose K100MCR and hydroxypropylmethylcellulose K15M. They also result, in the slowest release compared to similar other "polymers of similar molecular weight. Such a release pattern is desired for this aspect of the invention involving a hydrophilic matrix containing donepezil coated with water-insoluble polymer.

The hydrophilic matrix containing Donepezil can be prepared by direct compression, wet granulation, dry granulation such as roller compaction and slugging using equipments well-known to a person skilled in the art and also Remington's Pharmaceutical Sciences,18th edition, 1990, Mack publishing Company Easton, Pennysylvania 18042 (and even the recent editions) describe such processes for the preparation of solid dosage forms. For example, the granules can be made from Donepezil, hydrophilic matrix forming polymers and binder with an optional filler. Thereafter, the granules can be mixed with the hydrophilic matrix forming polymers and compressed into tablets which will subsequently be coated by a water-insoluble polymer membrane.
The water-insoluble polymer applied as a membrane in this case has the role to control the diffusion of donepezil in the surrounding medium. The water-insoluble polymer is selected from cellulose ethers, cellulose esters, methacrylic acid-acrylic acid copolymers and the like. More specifically, ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups and the like. Suitable release controlling amount of water-insoluble polymer may be from about 1 to 50% w/w or 1-15% w/w or 1-10% w/w or 1-5% w/w of the total weight of the formulation. For example, ethylcellulose with an ethoxyl content of 48-49.5% can be used in the form of a solution having the viscosity in the range of 5-110 mPa-s or 6-8 mPa-s or 9-11 mPa-s for a 5% solution in toluene: ethanol (80:20) at 25°C or 45-55 mPa-s for a 5% solution in toluene: ethanol (60:40) at 25°C. Any desired range of viscosity can be obtained by mixing different grades of ethylcellulose. The solvents for the solution include but are not limited to chlorinated aliphatic hydrocarbons such as dichloromethane, alcohols such as isopropanol or mixtures thereof. The control of diffusion can be significantly modulated. For example, the control of diffusion of an ethylcellulose membrane can be significantly modulated by inclusion of hydroxypropylmethylcellulose in the membrane.

Plasticizers can be included in the water-insoluble polymer membrane to provide a desired flexibility to the membrane in an amount of about 5-30% by weight of total solids in the solution. As an example, fatty acid esters, triethyl citrate, propylene glycol, polyethylene glycols such as polyethylene glycol 1500 and the like can be used as plasticizers. The amount of plasticizer may be 0-10% or 0-5% or 0-2% by weight of the formulation and usually depends on the amount of the polymer used. For example, in case of ethylcellulose film the amount of plasticizer would be about one-half the polymer total of the coating solution. The coating solution may additionally contain water soluble substances such as polyvinylpyrrolidone and the like.
In another aspect, the invention relates to a modified release formulation of Donepezil in the form of a matrix comprising Donepezil and at least one enteric polymer.
The enteric polymer matrix contains one or more enteric polymers. The enteric polymers may be present in a suitable amount of about 1 to 70% w/w or 1 to 30% w/w or 20-27% w/w of the total weight of the formulation. Examples of enteric polymers include, but are not limited to, suitable polymethacrylates (such as for example Eudragit® L, Eudragit ® S and the like), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), methyl cellulose acetate . phthalate, hydroxypropyl methyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose, cellulose acetate succinate, cellulose- acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, suitable poly (methylvinyl ether/maleic anhydride) copolymers

and derivatives, ethyl methacrylate-methylmethacrylate-chlorotrimethylammonium ethyl methacrylate copolymer, natural resins such as zein, shellac and the like. The choice of suitable enteric polymer depends on the pH at which the Donepezil release is desired. For example, in case of Eudragit® L 100-55 [Poly (methacrylic acid-co-ethyl acrylate) 1:1] the Donepezil release is targeted at a pH of 6-7 or in case of EUDRAGIT® S 100 (Poly (methacrylic acid, methyl methacrylate) 1:2) the Donepezil release is targeted at a pH greater than 7. Site specific Donepezil delivery in intestine by combinations of EUDRAGIT® L/S grades in a ratio of 0.1: 1 to 1:0.1.
The enteric polymer matrix containing Donepezil can be prepared by direct compression, wet granulation, dry granulation such as roller compaction and slugging using equipments well-known to a person skilled in the art. For example, the granules can be made from Donepezil, enteric polymers and binder with optional filler. Thereafter, the granules can be mixed with optional filler/s and lubricant and compressed into tablets which may or may not subsequently be coated by a water-insoluble polymer membrane. The water-insoluble polymer and coating thereof has been described above.
In another aspect, the invention relates to a modified release formulation of Donepezil in the form of an uncoated matrix comprising Donepezil, at least one water-insoluble polymer and at least one water-soluble resin.
The water-insoluble polymer and water-soluble resin matrix contains one or more water-insoluble polymers and one or more water-soluble resins. The water-insoluble polymer has the role to control the diffusion of donepezil in the surrounding medium. The water-insoluble polymers may be present in a suitable amount of about 1 to 50% w/w or 1 to 30% w/w or 10-15% w/w of the total weight of the formulation. The water-insoluble polymer/s" is/are selected from cellulose ethers,

cellulose esters, methacrylic acid-acrylic acid copolymers and the like. More specifically, ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups and the like. Suitable release controlling amount of water-insoluble polymer may be from 1 to 50% w/w or 1-15% w/w or 10-14% w/w of the total weight of the formulation. For example, ethylcellulose with an ethoxyl content of 45-46.5% and a having the viscosity in a solution in the range of 5-110 mPa-s or 45-55 mPa-s can be used. Any desired range of viscosity can be obtained by mixing different grades of ethylcellulose. On the other hand, polymethacrylates containing quaternary ammonium groups displaying pH independent swelling such as Eudragit® RL 30 D, Eudragit® RL PO, Eudragit® RL 100, Eudragit® RL 12.5, Eudragit® RS 30 D, Eudragit® RS PO, Eudragit® RS 100, Eudragit® RS 12.5 can be used. Depending on the permeability of the matrix desired and to obtain customized release profiles a combination of RL and RS grades in different ratios can be used. Eudragit® RL grades contain are poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) in a ratio of 1 : 2 : 0.2 and Eudragit® RS grades contain poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) in a ratio of 1: 2 : 0.1.
The water soluble resins included in the matrix have a role of fast hydration and gel formation. The water soluble resins may be present in a suitable amount of about 1 to 50% w/w or 1 to 30% w/w or 10-25% w/w of the total weight of the formulation. Suitable water-soluble resins such as nonionic poly (ethylene oxide) polymers can be used in the matrix. The poly (ethylene oxide) polymers have a viscosity in the range of about 1600-10,000 cP in a 1% solutions 25°C, cP or 400-4000 cP in a 2% solution or 30-17,750 cP in a 5% solution. The high viscosity poly (ethylene oxide) polymers are preferred to be used and any desired viscosity can be obtained by mixing two or more different viscosity grades of poly (ethylene oxide) polymers.

The water-insoluble polymer and water-soluble resin matrix containing Donepezil can be prepared by direct compression, wet granulation, dry granulation such as roller compaction and slugging using equipments well-known to a person skilled in the art. For example, the granules can be made from Donepezil, water-insoluble polymer, water-soluble resin and binder with optional filler. Thereafter, the granules can be mixed with optional filler/s and lubricant and compressed into tablets which may or may not subsequently be coated by a water-insoluble polymer membrane. The water-insoluble polymer and coating thereof has been described above.
In another aspect, the invention relates to a modified release formulation of Donepezil in the form of a hydrophilic matrix comprising Donepezil, allyl ethers of pentaerythritol, at least one water-insoluble filler and optionally at least one water soluble polymer.
The hydrophilic matrix contains allyl ethers of pentaerythritol which are highly efficient controlled release agents in both monolithic and multiparticulate systems. They offer formulation flexibility in that, they can be used alone or in synergy with other controlled release excipients such as for example various grades of hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, sodium alginates, starches and the like. Also they are compatible with commoniy used tablet excipients. They can serve wide variety of functions such as-providing good tablet hardness and low friability over a wide range of compression forces, acting as binders in dry and wet granulation processes, attributing other properties like bioadhesion and taste-masking to the formulations. Notable among the allyl ethers of pentaerythritol are granular forms such as Carbopol® 71G NF and powder forms such as Carbopol® 974P NF. Carbopol® 71G NF which is lightly cross-linked can be used in direct compression processes due to its improved flow properties. These allyl ethers of pentaerythritol (allyl ether polymers) swell up to

1,000 times their original volume in water to form a gel when exposed to a pH environment above their pKa. The release of Donepezil from tablets with allyl ether polymers is controlled by diffusion of Donepezil through the gel layer that they form in contact with aqueous medium. When the allyl ether polymer containing formulation such as Donepezil containing tablet is placed in contact with a dissolution medium; Donepezil in the outside layer exposed to the bathing solution is dissolved and then diffuses out of the matrix. The allyl ether polymers swell to form a hydrated matrix layer containing discrete microgels made up of many polymer particles in which the Donepezil is dispersed The hydrated matrix layer controls water penetration (into the non-hydrated core) and diffusion of Donepezil through the hydrated matrix. Donepezil release from allyl ether polymer matrices may be medium-dependent due to the anionic nature of the polymer. The swelling and gel formation of the polymers is pH dependent. At lower pH values the polymer is not fully swollen and the Donepezil is released faster. As the pH increases, swelling of the polymer is greater resulting in rapid formation of the gel layer which prolongs donepezil release. However, the pH effect "on the polymer does not significantly impact Donepezil release in various media. The significant factor affecting the release of Donepezil is the effect of pH on its solubility. Increasing the level of allyl ether polymer in a formulation leads to slower and more linear release of Donepezil. To achieve desired release profile for the donepezil formulation, the allyl ether/s polymer/s can be present in a suitable amount of about 5-30 %w/w or 5-15 % w/w or 15- 30 % w/w of the weight of the formulation. For a matrix formulation of Donepezil, prepared by wet granulation process, the powder grades of Carbopol® polymers may be preferred, over granular grades of Carbopol® polymers which may be more suitable for a direct compression or dry granulation process. It is notable, that the amount of Carbopol polymers in the Donepezil formulation is dictated by the polymer surface area which is inversely proportional to the amount of Carbopol® polymers required in the formulation. However the amount of allyl ether polymer

needed in the matrix formulation can be lowered by the incorporating water soluble polymers in the matrix like hydroxypropylmethylcellulose having nominal viscosity in 2% w/v aqueous solutions of about 4000-100,000 mPas at 20°C; available commercially as Methocel K4M Premium and Methocel® K100M Premium. These water soluble polymers can be present in a suitable amount of upto about 5 times the weight of the allyl ether polymers in the formulation depending upon the type of release of Donepezil desired. Preferably, the water soluble polymers may be present in an amount from about 2-4 times the weight of the allyl ether polymers.
The water insoluble fillers are suitable for the hydrophilic matrix formulations of allyl ether polymers. Suitable water insoluble fillers include starch and starch derivatives other than pregelatinized starch, such as com starch, rice starch, wheat starch or potato starch and the like. Examples of other water insoluble fillers include microcrystalline cellulose, dibasic calcium phosphate dihydrate, anhydrous dibasic calcium phosphate and the like. The water insoluble fillers, preferably corn starch, can be used with or in place of water soluble fillers. The total weight percentage of filler ranges from about 5 - 75%w/w or 20-60 %w/w or 40-55%w/w of the total weight of the formulation.
The hydrophilic matrix containing Donepezil, allyl ether polymer and at least one water insoluble filler can be prepared by direct compression, wet granulation, dry granulation such as roller compaction and slugging using equipments well-known to a person skilled in the art. For example, the granules can be made from Donepezil, allyl ether polymer, water insoluble filler with optional water soluble polymer. Thereafter, the granules can be mixed with optional filler/s and lubricant and compressed into tablets which may or may not subsequently be coated by a water-insoluble polymer membrane. The water-insoluble polymer and coating thereof has been described above. Also another method-involves mixing of the Donepezil, allyl

ether polymer, water insoluble filler with optional water soluble polymer. This mixture can be compacted after optional pre-lubricating with a glidants such as silicon dioxide and lubricating with a lubricant to form tablets or the compacts can be slugged and after optional pre-lubricating with a glidants such as silicon dioxide and lubricating with a lubricant, compacted to form tablets. These compressed tablets may or may not subsequently be coated by a water-insoluble polymer membrane, The water-insoluble polymer and coating thereof has been described above.
The formulations as described above of this invention may be granules, multiparticulates, tablets, caplets, capsules or mini-tablets. Preferably the formulations as described above may be formulated as tablets or as mini-tablets to be filled in capsules. The formulations may additionally contain pharmaceutically acceptable excipients including binders, diluents, surfactants, lubricants/glidants, coloring agents and the like.
Suitable binders include, for example, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol and the like or mixtures thereof.
Suitable diluents include, for example, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, compressible sugars and the like or mixtures thereof.
Suitable surfactants include, for example, both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants such as sodium lauryl sulfate, poloxamers (copolymers

of polyoxyethylene and polyoxypropylene), natural or synthetic lecitins, sorbitan esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene stearates or mixtures thereof.
Suitable lubricants/glidants include, for example, colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax, sodium stearyl fumarate and the like.
Coloring agents include any FDA approved colors for oral use.
Suitable solvents for the formulation processes such as wet granulation and coating can be selected from solvents such as water, isopropanol, ethanol, dichloromethane and the like.
The coating solutions may be applied using techniques, such as spray coating in a conventional coating pan or fluidized bed processor or dip coating as known to person skilled in the art.
The dissolution studies of the formulations -of this invention can be performed by suitable dissolution methods as per US pharmacopoeia such as for example, the dissolution studies of tablet formulations can be performed using following method. USP apparatus II, at 50 rpm using 900 ml 0.1 N HCL as a medium.
The examples mentioned below, demonstrate some illustrative procedures for preparing the pharmaceutical composition as described herein. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

EXAMPLE 1

Ingredient mg/ tablet % w/w
INTRAGRANULAR
Donepezil Hydrochloride 23.00 12.53
Mannitol 106.00 57.73
Lactose monohydrate 30.00 16.34
Povidone K 90 4.00 2.18
Purified Water q.s. q.s.
EXTRAGRANULAR
Magnesium Stearate LOO 0.54
COATING 1
Ethylcellulose 10 cps 4.00 2.18
Povidone K 90 2.40 1.31
Polyethylene glycol 1500 1.60 0.87
Isopropyl alcohol q.s.
Dichloromethane q.s.
COATING 2
Eudragit®L 100-55* 6.60 3.59
Triethyl citrate 1.20 0.65
Silicon Dioxide 3.00 1.63
Polyethylene glycol 1.20 0.65
Isopropyl alcohol q.s.
Dichloromethane q.s.
COATING 3
Opadry white YS-1-7040S 3.60 1.96
Isopropyl alcohol q.s.

Ingredient mg/ tablet % w/w
Dichloromethane q.s.
Tablet weight 183.60 100
* Eudragit® L 100-55 is Poly (methacrylic acid-co-ethyl acrylate) 1:1
$ Opadry white YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium
dioxide)
Process-
1) Donepezil hydrochloride, mannitol and lactose monohydrate were passed through 30 mesh stainless steel sieve and mixed for 10 minutes in a rapid mixer granulator.
2) Povidone K 90 was dissolved in a sufficient amount of purified water and used to granulate the contents of step 1. The granules were dried and sifted through 1.0 mm stainless steel screen.
3) After milling, the milled granules were lubricated with magnesium stearate in a blender for 5 minutes.
4) The lubricated granules were compressed using 7.0 mm punches.
5) Ethyl cellulose 10 cps, povidone K 90 and polyethylene glycol 1500 were dissolved in isopropyl alcohol and dichloromethane mixture under stirring to get a clear solution.
6) The compressed tablets of step 4 were coated with the solution prepared in step 5 and dried.
7) Eudragit® LI00-55, triethyl citrate, polyethylene glycol and silicon dioxide were dispersed in isopropyl alcohol and dichloromethane mixture under stirring to get suspension.
8) The functionally coated tablets of step 6 were coated with the suspension prepared in step 7.

9) The coated tablets of step 8 were further coated with opadry white YS-1-7040 suspension and dried.
10) The above tablets were evaluated for dissolution using following method. USP apparatus II, 50 rpm, 900 ml 0.1 N HCL

Time in hrs. % Drug Release
1 4.0
2 18.0
4 40.0
8 61.0
12 78.0
16 86.0
24 102.0
EXAMPLE 2

Ingredient mg/tablet % w/w
INTRAGRANULAR
Donepezil Hydrochloride 23.00 11.06
Hydroxypropylmethylcellulose Kl 00MCR 15.00 7.21
Hydroxypropylmethy] cellulose K15M 20.00 9.62
Lactose monohydrate 115.00 55.29
Hydroxypropylcellulose 5.00 2.40
Isopropyl alcohol q.s. q.s.
EXTRAGRANULAR
Hydroxypropylmethylcellulose K100 MCR 10.00 4.81

Ingredient mg/tablet %w/w
Hydroxypropylmethylcellulose K15M 10.00 4.81
Magnesium Stearate 2.00 0.96
COATING
Ethylcellulose 10 cps 4.00 1.92
Povidone K 90 2.40 1.15
Polyethylene glycol 1500 1.60 0.77
Isopropyl alcohol q.s. q.s.
Dichloromethane q.S. q.s.
Tablet weight 208.00 100
Process-
1) Donepezil hydrochloride, hydroxypropylmethylcellulose K100MCR, hydroxypropylmethylcellulose K15M and lactose monohydrate were passed through 30 mesh stainless steel sieve and mixed for 10 minutes in a rapid mixer granulator.
2) Hydroxypropylcellulose was dissolved in a sufficient amount of Isopropyl alcohol used to granulate the contents of step 1. The granules were dried and sifted through 1.0 mm (18 mesh) stainless steel screen.
3) After milling the granules were mixed with hydroxypropylmethylcellulose K100MCR, hydroxypropylmethylcellulose K15M and lubricated with magnesium stearate in a blender for 5 minutes.
4) The lubricated granules were compressed using 9.0 mm punches.
5) Ethylcellulose 10 cps, povidone K 90 and polyethylene glycol 1500 were dissolved in isopropyl alcohol and dichloromethane mixture under stirring to get a clear solution.

6) The compressed tablets of step 4 were coated with the solution prepared in step 5 and dried.
EXAMPLE 3

Ingredient mg/tablet % w/w
Donepezil Hydrochloride 23.00 11.50
Eudragit®Ll0055* 25.00 12.50
Eudragit® S 100s 25.00 12.50
Microcrystalline cellulose 120.00 60.00
Hydroxypropyl cellulose 5.00 2.50
Isopropyl alcohol q.s. q.s.
Magnesium Stearate 2.00 1.00
Tablet weight 200.00 100
# Euit®drag S 100 is Poly (methacrylic acid, methyl methacrylate) 1:2
* Eudragit® L 100-55 is Poly (methacrylic acid-co-ethyl acrylate) 1:1
Process-
1) Donepezil hydrochloride, Eudragit® L 100 55, Eudragit® S 100 and microcrystalline cellulose were passed through 30 mesh stainless steel sieve. And mixed for 10 minutes in a rapid mixer granulator.
2) Hydroxypropylcellulose was dissolved in a sufficient amount of Isopropyl alcohol used for granulating the contents of step 1. The granules were dried and sifted through 1.0 mm (18 mesh) stainless steel screen.
3) After milling the granules were lubricated with magnesium stearate in a blender for 5 minutes.
4) The lubricated granules were compressed using 9.0 mm punches.

The above tablets were evaluated for dissolution using following method. USP apparatus II, 50 rpm, 900 ml 0.1 N HCL

Time in hrs. % Drug Release
1 12.0
2 18.0
4 35.0
8 56.0
12 65.0
16
24 77.0 82.0
EXAMPLE 4

Ingredient mg/Tablet %w/w
Donepezil Hydrochloride 23.00 11.50
Ethylcellulose 50 cps 25.00 12.50
Polyethylene oxide WSR-303 ** 40.00 20.00
Microcrystalline cellulose 105.00 52.50
Hydroxypropylcellulose 5.00 2.50
Isopropyl alcohol q.s. q.s.
Magnesium Stearate 2.00 1.00
Tablet weight 200.00 100
**Polyethylene oxide WSR-303 is nonionic poly (ethylene oxide) polymer with a viscosity of 7,500 - 10,000 cP in a 1% solution at 25°C.

Process-
1. Donepezil hydrochloride, ethylcellulose, polyethylene oxide and microcrystalline cellulose were passed through 30 mesh stainless steel sieve and mixed for 10 minutes in a rapid mixer granulator.
2. Hydroxypropylcellulose was dissolved in sufficient amount of isopropyl alcohol and used to granulate the contents of step 1. The granules were dried and sifted through 1.0 mm (18 mesh) stainless steel screen.
3. After milling the granules were lubricated with magnesium stearate in a blender for 5 minutes.
4. The lubricated granules were compressed using 9.0 mm punches.
The above tablets were evaluated for dissolution using following method. USP apparatus II, 50 rpm, 900 ml 0.1 N HCL

Time in hrs % Drug Release
1 4.0
2 15.0
4 26.0
8 46.0
12 55.0
16 67.0
24 72.0

Ingredient
mg/ tablet % w/w
INTRAGRANULAR
Donepezil Hydrochloride 18.00 9.80
Mannitol 106.00 57.73
Lactose monohydrate 30.00 16.34
Povidone K 90 4.00 2.18
Purified Water q.s. q.s.
EXTRAGRANULAR
Magnesium Stearate 1.00 0.54
COATING 1
Ethylcellulose 10 cps 4.00 2.18
Povidone K 90 2.40 1.31
Polyethylene glycol 1500 1.60 0.87
Isopropyl alcohol q.s.
Dichloromethane q.s.
COATING 2
Eudragit®L 100-55* 6.60 3.59
Triethyl citrate 1.20 0.65
Silicon Dioxide 3.00 1.63
Polyethylene glycol 1.20 0.65
Isopropyl alcohol q.s.
Dichloromethane q.s.
COATING 3
Donepezil hydrochloride 5.00 2.72
Opadry white YS-1-7040 3.60 1.96
Isopropy] alcohol q.s.
Dichloromethane q.s.

Ingredient mg/ tablet % w/w
Tablet weight 183.60 100
* Eudragit® L 100-55 is Poly (methacrylic acid-co-ethyl acrylate) 1:1 $ Opadry white YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide) Process-
1. Donepezil hydrochloride, mannitol and lactose monohydrate were passed through 30 mesh stainless steel sieve and mixed for 10 minutes in a rapid mixer granulator.
2. Povidone K 90 was dissolved in a sufficient amount of purified water and used ro granulate the contents of step 1. The granules were dried and sifted through 1.0 mm stainless steel screen.
3. After milling, the milled granules were lubricated with magnesium stearate in a blender for 5 minutes.
4. The lubricated granules were compressed using 7.0 mm punches.
5. Ethyl cellulose 10 cps, povidone K 90 and polyethylene glycol 1500 were dissolved in isopropyl alcohol and dichloromethane mixture under stirring to get a clear solution.
6. The compressed tablets of step 4 were coated with the solution prepared in step 5 and dried.
7. Eudragit® LI 00-55, triethyl citrate, polyethylene glycol and silicon dioxide were dispersed in isopropyl alcohol and dichloromethane mixture under stirring to get suspension.
8. The functionally coated tablets of step 6 were coated with the suspension prepared in step 7.

9. The coated tablets of step 8 were further coated with donepezil hydrochloride in opadry white YS-1-7040 suspension and dried.
EXAMPLE 6

Ingredients Quantity in mg %w/w
Donepezil HCJ -23 6.76
Carbopol®974PNF## 30 8.82
Corn Starch 180 52.94
Hydroxypropylmethylcellulose K100M 100 29.41
Colloidal silicon dioxide - 3 0.88
Magnesium stearate 4 1.18
Tablet weight 340 100.00
## Carbopol® 974P NF is allyl ethers of pentaerythritol. Process-
1. Donepezil hydrochloride, Carbopol® 974P NF, corn starch and Hydroxypropylmethylcellulose K100M were mixed geometrically and passed through 20 mesh stainless steel sieve.
2. The above mixture was added to a conta blender and mixed for 5 minutes
3. Colloidal silicon dioxide was added to the above mixture in the conta blender and mixed for 10 minutes.

4. The above mixture was lubricated by adding magnesium stearate (passed through 60 mesh sieve) to the conta blender with and mixing for 5 minutes.
5. The lubricated blend was compressed to form tablets.