FIELD OF INVENTION

The invention relates to extended-release pharmaceutical compositions comprising donepezil or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient and to their process of preparation.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Donepezil is an acetylcholinesterase inhibitor, available in its hydrochloride form and is indicated for the treatment of dementia of'the Alzheimer's type. It is marketed in US under the brand name of Aricept ™ and Aricept ODT ™. Donepezil hydrochloride is a basic drug that exists as a white crystalline powder and is soluble in water.

Donepezil has an unpleasant bitter taste. The fast dissolving formulations of donepezil requires taste masking agents to mask its unpleasant taste. The basic nature of donepezil shows a fluctuation in its release profile. Immediate release compositions also involve repeated dosing leading to drug accumulation. To overcome such problems a number of techniques have been developed, out of which development of extended release composition is one.

Prior art literature relating to extended-release compositions of donepezil are disclosed below.

US 2008/0213368 discloses a method for stabilizing an anti-dementia drug, comprising adding a high molecular weight acidic substance into a pharmaceutical composition comprising the anti-dementia drug and a high molecular weight basic substance.

US 2010/0016362 relates to a pharmaceutical composition containing donepezil or a pharmaceutically acceptable salt thereof and a naturally-occurring polymer along with a stabilizer and the process for producing the same.

US 2009/0208579 discloses a matrix type sustained-release preparation containing a basic drug or a salt thereof, more specifically, relates to a preparation which not only inhibits the initial drug burst (rapid drug release immediately after dissolution) in a dissolution test, but also ensures dissolution with low pH dependence of the basic drug or the salt thereof at the early stage of dissolution, in the dissolution test.

WO 2009/001146 discloses a pharmaceutical composition for oral administration comprising donepezil or pharmaceutically acceptable salt thereof, and an effective amount of pH-dependent excipient as a taste masking agent, to suppress the release of donepezil in the pH environment of the oral cavity and increase the release of donepezil in acidic environment.

Though the above prior art disclose extended-release compositions of donepezil, still there is a need for developing improved extended-release composition of donepezil.

The invention relates to such improved extended-release composition of donepezil and its process of preparation.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to extended-release compositions comprising donepezil or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient and to their process of preparation.

An aspect of the invention provides matrix type extended-release pharmaceutical compositions comprising donepezil or its pharmaceutically acceptable salts thereof and one or more other pharmaceutically acceptable excipients.

Another aspect of the invention provides process for preparing matrix type extended-release pharmaceutical compositions comprising donepezil or its pharmaceutically acceptable salts thereof and one or more other pharmaceutically acceptable excipients.

Yet another aspect of the invention provides matrix-in-reservoir type extended-release pharmaceutical compositions comprising donepezil or its pharmaceutically acceptable salts thereof and one or more other pharmaceutically acceptable excipients.

An aspect of the invention provides process for preparing matrix-in-reservoir type extended-release pharmaceutical compositions comprising donepezil or its pharmaceutically acceptable salts thereof and one or more other pharmaceutically acceptable excipients.

An aspect of the invention relates to invitro drug release profiles of the compositions prepared according to the invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to extended-release compositions comprising donepezil or its pharmaceutically acceptable salts thereof and one or more other pharmaceutically acceptable excipients and to their process of preparation.

The invention also relates to matrix type extended-release pharmaceutical compositions comprising donepezil or its pharmaceutically acceptable salts thereof and one or more other pharmaceutically acceptable excipients and to their process of preparation.

The invention further relates to matrix-in-reservoir type extended-release compositions comprising donepezil or its pharmaceutically acceptable salts thereof and one or more other pharmaceutically acceptable excipients and to their process of preparation.
The term "composition" as used herein refers to equivalents thereof, including but not limited to: cores, coated cores, pellets, micro-pellets, pills, compressed tablets, granules, spheres, capsules and the like.

The term "excipient" as used herein refers to any ingredient that may be added to the formulation besides the active ingredient.

The term "matrix type" as used herein refers to a composition wherein the drug is uniformly dispersed or distributed in a rate controlling polymer."

The term "matrix-in-reservoir type" as used herein refers to a composition wherein the drug is uniformly dispersed or distributed in a rate-controlling polymer to form a matrix, which is further surrounded by an extended-release coating layer.

The composition of the invention can be formulated as solid compositions for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferably, the composition is in the form of tablets.
The composition of the invention in addition to the active ingredient may comprise one or more pharmaceutically acceptable excipients which include, but are not limited to diluents, lubricants, binders, surfactants, release controlling polymers, film former, plasticizers, coloring agent, flavoring agents, sweetening agent, viscosity enhancers, preservatives, antioxidants and the like.

Diluents used include, but are not limited to microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like.
Lubricants which include, but are not limited to colloidal silicon dioxide, talc, stearic acid and its salts.

Binders used include, but are not limited to acacia, alginic acid, carbomer copolymer, carbomer interpolymer, copovidone, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, glucose (liquid), guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyethylene oxide, polyvinylpyrrolidone, povidone, starch, or sodium carboxymethylcellulose and the like.

Release-controlling or rate-controlling polymers include, but are not limited to hydrophilic or water-soluble or hydrophobic polymers, or a combination thereof. The hydrophilic polymers include N-vinylpyrrolidone, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxy propylcellulose, vinyl and acrylic polymers; polyacrylic acid and the like. The hydrophobic materials include ethyl cellulose, low hydroxylpropyl cellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, polyalkyl methacrylates, polyalkyl acrylates, crosslinked vinylpyrrolidone polymers, hydrogenated castor oil, stearic acid, Gelucire ™ and the like.

The extended-release coat may comprise hydrophilic or hydrophobic materials, or a combination thereof. The hydrophilic material includes copolyvidone, polyvinyl pyrrolidone, polyethylene glycols, hydroxyethyl cellulose, hydroxypropyl methylcellulose and the like. The hydrophobic materials include but are not limited to cellulose ether such as ethyl cellulose, cellulose acetate, polyvinyl acetate, methacrylic acid esters neutral polymer, polyvinyl alcohol-maleic anhydride copolymers, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, crosslinked vinylpyrrolidone polymers, stearic acid, alginic acid, pectin, carboxyvinyl polymer, carboxymethyl cellulose and the like. Commercially available dispersion of film formers namely, Eudragit L-30D, Eudragit NE 30D, Aquacoat ECD-30, Surelease E-7, Eudragit RS 30D, Eudragit RL 30D, NS enteric ™ etc. may be used for the purpose of providing extended-release coating layer.

Plasticizers that may be used in the coating composition include, but are not limited to, acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, triacetin, tributyl citrate, or triethyl citrate.

The tablets according to this invention are prepared by techniques such as wet granulation or dry granulation or direct compression.

The wet granulation process involves the steps a) mixing and blending donepezil along with diluent and the rate controlling polymers b) preparing the binder solution c) granulating the prepared blend of step (a) with binder solution of step (b) followed by drying d) lubricating the prepared granules followed by compression in to tablet which may be optionally film coated.

The dry granulation process involves the steps a) mixing and blending of donepezil along with diluent and the rate controlling polymers followed by preparation of slugs or compacts b) milling of the prepared slugs or compacts followed by screening to get granules c) lubricating the prepared granules followed by compression in to tablets which may be optionally film coated.

The direct compression process involves a) mixing donepezil together with all the other excipients including rate controlling polymers b) compression of the prepared blend in to tablets followed by an optional film coating layer.

Preferably, the compositions of the invention are prepared by dry granulation process which essentially includes the following steps:

a) mixing donepezil, water-soluble polymer and optionally one or more pharmaceutically acceptable excipient to form a blend ;

b) compacting said blend from step (a) in a roll-compactor to get compacts;

c) milling said compacts from step (b) to get granules;

d) lubricating said granules from step (c); and

e) compressing said granules from step (d) in to tablets.

In case of matrix-in-reservoir type compositions the prepared tablets are further coated with extended-release coating layer. The coating composition can be prepared by dispersing the coating polymers in aqueous solvent. The prepared extended-release coating dispersion is sprayed on the compressed tablets.

The invention also provides invitro dissolution study of the prepared tablets using USP Type-II apparatus, in both pH 6.8 phosphate buffer and 0.1 N HC1.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Table

Brief Manufacturing Process for Examples 1&4:

1. Donepezil HC1, lactose monohydrate and hydroxy propylmethyl cellulose were sifted through suitable screen and mixed it properly for sufficient period of time.

2. The above material was compacted using roll compactor.

3. Compacts obtained from the above step were milled using quadracomil fitted with suitable screen.

4. Granules obtained from the above step were sifted through suitable screen.

5. Granules obtained from the above step were lubricated with presifted magnesium stearate

6. Blend of above step was compressed to tablets.

Brief Manufacturing Process for Examples 2, 3, 5, 6&7:

1. Donepezil HC1, lactose monohydrate and hydroxy propylmethyl cellulose were sifted through suitable screen and mixed it properly for sufficient period of time.

2. The above material was compacted using roll compactor.

3. Compacts obtained from the above step were milled using quadracomil fitted with suitable screen.

4. Granules obtained from the above step were sifted through suitable screen.

5. Granules obtained from the above step were lubricated with presifted magnesium stearate.

6. Blend of above step was compressed to tablets.

7. Tablets were coated with the composition containing Surelease™, NS Enteric™ and hydroxy propylmethyl cellulose.

Dissolution Study:

The tablets prepared according to the invention were studied for drug release profile as given below:

Table-1

900 mL of 0.1N HC1, USP Type -II (Paddle), 50 RPM

Table-2

900 mL of pH 6.8 Phosphate, USP Type -II (Paddle), 50 RPM

WE CLAIM:

1. An extended-release pharmaceutical composition comprising donepezil or its pharmaceutically acceptable salts thereof, a water-soluble polymer and optionally one or more other pharmaceutically acceptable excipients, wherein said composition is a matrix type composition.

2. An extended-release pharmaceutical composition comprising donepezil or its pharmaceutically acceptable salts thereof, a water-soluble polymer, optionally one or more other pharmaceutically acceptable excipients, and an extended-release coating layer, wherein said composition is a matrix-in-reservoir type composition.

3. The extended-release pharmaceutical composition according to claim 1 or 2, wherein said composition is a tablet.

4. The extended-release pharmaceutical composition according to claim 1 or 2, wherein said water-soluble polymer is selected from a group consisting of N-vinylpyrrolidone, hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, or combinations thereof.

5. The extended-release pharmaceutical composition according to claim 2, wherein said extended-release coating layer comprises polymers selected from a group consisting of ethyl cellulose, cellulose acetate, polyvinyl acetate, cellulose acetate phthalate, stearic acid, NS Enteric™ or combinations thereof.

6. The extended-release pharmaceutical composition according to claim 1 or 2, wherein said other pharmaceutically acceptable excipients are selected from a group consisting of diluents, binders, surfactants, glidants and lubricants and combinations thereof.

7. A process for preparing a matrix type extended-release pharmaceutical tablet comprising donepezil or its pharmaceutically acceptable salts, a water-soluble polymer and optionally one or more pharmaceutically acceptable excipients, wherein said process involves the steps of:

a) mixing donepezil, water-soluble polymer and optionally one or more pharmaceutically acceptable excipient to form a blend ;

b) compacting said blend from step (a) in a roll-compactor to get compacts;

c) milling said compacts from step (b) to get granules;

d) lubricating said granules from step (c); and

e) compressing said granules from step (d) in to tablets

8. A process for preparing a matrix-in reservoir type extended-release pharmaceutical tablet comprising donepezil or its pharmaceutically acceptable salts, a water-soluble polymer, optionally one or more pharmaceutically acceptable excipients and an extended-release coating layer, wherein said process involves the steps of:

a) mixing donepezil, water-soluble polymer and optionally one or more pharmaceutically acceptable excipient to form a blend ;

b) compacting said blend from step (a) in a roll-compactor to get compacts;

c) milling said compacts from step (b) to get granules;

d) lubricating said granules from step (c);

e) compressing said granules from step (d) in to tablets; and

f) coating said tablets of step (e) with an extended-release polymer.

9. An extended-release pharmaceutical composition comprising:

wherein said composition is a matrix type composition.

10. An extended-release pharmaceutical composition comprising:

wherein said composition is a matrix-in-reservoir type composition.