WO2011064797A2

WO2011064797A2 - Controlled release pharmaceutical compositions of galantamine

Info

Publication number: WO2011064797A2
Application number: PCT/IN2010/000767
Authority: WO
Inventors: Ashok Omray; Sandhya Rajendra Shenoy; Harish Tulsidutt Bhatt
Original assignee: Usv Limited
Priority date: 2009-11-26
Filing date: 2010-11-26
Publication date: 2011-06-03
Also published as: CA2781826A1; WO2011064797A3; EP2503996A2; BR112012012766A2

Abstract

Disclosed are controlled release pharmaceutical compositions of Galantamine comprising a plurality of matrix mini tablets comprising Galantamine or its pharmaceutically acceptable salt and at least one release modifying agent. Said compositions are characterized by the absence of release rate modifying coating and/or absence of an immediate release portion of the Galantamine.

Description

"Controlled release pharmaceutical compositions of Galantamine" Related application:

This application claims the benefit of Indian Provisional Application No.

2736/MUM/2009 filed on 26 November 2009.

Technical Held of the invention:

The present invention relates to controlled release pharmaceutical compositions of Galantamine and process of preparation of said compositions.

Background of the invention:

Galantamine is indicated for the treatment of mild to moderately severe dementia of the Alzheimer type. Galantamine is a tertiary alkaloid and is a competitive and reversible inhibitor of acetylcholinesterase. Galantamine hydrobromide is chemically (4aS,6R,8aS)-4a,5,9,10, l l ,12-hexahydro-3-methoxy-l l-methyl-6H-benzofuro 3a,3,2- efj [2]benzazepin-6-ol hydrobromide. The empirical formula of Galantamine hydrobromide is Ci7H₂iN0₃.HBr and it has a molecular weight of 368.27. Galantamine hydrobromide is a white to almost white powder and is sparingly soluble in water. The structural formula for Galantamine hydrobromide is as represented in Formula I,

Formula I

Galantamine hydrobromide is available in the form of tablets and capsules for the use in the treatment of Alzheimer's disease. Galantamine and its salts have also been employed in the treatment of a variety of disorders including alcoholism, nicotinic dependence and mania due to their affinity for nicotinic receptors and it is capable of passing the blood-brain barrier. Galantamine hydrobromide is marketed as Razadyne^® in US by Janssen pharmaceuticals and Reminyl^® in Europe by Shire pharmaceuticals.

Galantamine hydrobromide is also available in the form of extended release capsules and is marketed in United states by Janssen pharmaceuticals. Galantamine hydrobromide extended release capsules (Innovator) are available as opaque hard gelatin extended-release capsules of 8 mg (white), 16 mg (pink), and 24 mg (caramel) containing Galantamine hydrobromide, equivalent to respectively 8, 16 and 24 mg Galantamine base. The inactive ingredients include gelatin, diethyl phthalate, ethylcellulose, hypromellose, polyethylene glycol, titanium dioxide and sugar spheres (sucrose and starch). The 16 mg capsule also contains red ferric oxide. The 24 mg capsule also contains red ferric oxide and yellow ferric oxide. In Europe, the extended release capsules of Galantamine hydrobromide are marketed under the brand name 'Reminyl XL^®' by Shire pharmaceuticals.

Prior art discloses several formulations of Galantamine. Various attempts have been made to improve the characteristics of controlled release formulation of Galantamine.

EP0236684 discloses the use of Galantamine or an analogue or a pharmaceutically acceptable acid addition salt thereof for preparing a medicament for the treatment of Alzheimer's disease or related dementias.

WO0038686 discloses a controlled release formulation containing Galantamine, wherein it includes particles comprising Galantamine or a pharmaceutically acceptable acid addition salts thereof, a water-soluble pharmaceutically acceptable additive and optionally other pharmaceutically acceptable additives. The particles are coated by a release rate controlling membrane coating.

CA1326632 discloses a sustained release formulation wherein the particles of Galantamine hydrobromide are coated with polyvinyl pyrrolidone or any other suitable coating agent that is soluble in the intestinal tract.

US2004/0097484 discloses once a day pharmaceutical composition of Galantamine hydrobromide comprising a gelling agent, such as water-soluble organic gums, natural clays, synthetic clays to form a controlled release dosage form, such as a matrix, or diffusion-controlled composition.

WO2005048979 discloses process for preparation of modified release pharmaceutical composition consisting of casing comprising at least two micro tablets, which are coated with rate controlling agent(s) optionally in combination with auxiliary pharmaceutical additive(s), wherein each micro tablet comprises core particles comprising pharmaceutically active ingredient and rate controlling agent(s), said core particles optionally coated with rate controlling agent(s).

Prior art teaches various formulations involving multiple step processes and tedious techniques such as release rate controlling coating of the mini-tablets, pellets or granules; leading to an increased cost of production and thereby rendering the product quite expensive.

In view of the aforementioned drawbacks associated with prior art compositions it is apparent that there still exists a need for developing controlled release compositions which would ameliorate the aforementioned drawbacks.

The inventors of the present invention have developed Galantamine controlled release compositions which overcome the above drawbacks of prior art.

Object of Invention:

One object of the present invention is to provide controlled release pharmaceutical compositions of Galantamine comprising a plurality of matrix mini tablets, each comprising the active ingredient Galantamine hydrobromide and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty capsule shell.

Another object of the invention is to provide a process for preparation of controlled release pharmaceutical compositions of Galantamine, which utilizes the technique that controls the release of Galantamine and significantly reduces the side effect, associated with conventional immediate release dosage forms.

Another object of the invention is to provide a controlled release dosage form which is easy to prepare and economical and gives accurate dosing with better patient compliance.

Yet another object of the invention is to provide controlled release compositions of Galantamine that can be given twice a day or more preferably can be given once a day and that demonstrates reliable release rate and facilitated in-vivo absorption for desired period of time.

Summary of Invention:

The present invention provides controlled release pharmaceutical compositions of Galantamine useful for the treatment of mild to moderately severe dementia of Alzheimer type. Particularly, said composition comprises a plurality of controlled release mini tablets; wherein the mini tablet is in the form of a matrix mini tablet, which may optionally have a non-functional coating.

In one aspect, the present invention provides controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets, each comprising the active ingredient and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each matrix mini tablet comprises:

(a) Galantamine or a pharmaceutically acceptable salt thereof and

(b) at least one of the release modifying agents selected from: (i) one or more water soluble materials;

(ii) one or more water insoluble materials or

(iii) one or more water swellable materials.

In one aspect, the invention provides controlled release pharmaceutical compositions of Galantamine, wherein said composition is characterized by the absence of release rate modifying coating. Preferably, said compositions are characterized by the absence of a rate controlling polymer in the coat of the mini-tablet/pellet.

In another aspect, the invention provides controlled release pharmaceutical compositions of Galantamine, wherein said composition is characterized by the absence of an immediate release portion of the active ingredient Galantamine.

In another aspect, the invention provides controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets, each comprising the active ingredient Galantamine and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each matrix mini tablet comprises:

(a) Galantamine or a pharmaceutically acceptable salt thereof and

(b) at least one of the release modifying agent selected from:

(i) one or more water soluble material;

(ii) one or more water insoluble material or

(iii) one or more water swellable material;

wherein said composition exhibits a dissolution profile such that up to 2 hours, not more than 60% of Galantamine hydrobromide is released; after 4 hours, about 50% to 80% of Galantamine hydrobromide is released; after 12 hours, not less than 80% of Galantamine hydrobromide is released at pH 6.5 Phosphate buffer using USP Type II apparatus at 50 revolutions per minute.

In yet another aspect, the invention provides controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets, each comprising the active ingredient Galantamine and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each matrix mini tablet comprises:

(a) Galantamine or a pharmaceutically acceptable salt thereof and

(b) at least one of the release modifying agent selected from:

(i) one or more water soluble material;

(ii) one or more water insoluble material or

(iii) one or more water swellable material;

wherein said composition is characterized by the absence of release rate modifying coating; and/or

wherein said composition is characterized by the absence of an immediate release portion of the active ingredient Galantamine; and/or

wherein said composition exhibits a dissolution profile such that up to 2 hours, not more than 60% of Galantamine hydrobromide is released; after 4 hours, about 50% to 80%) of Galantamine hydrobromide is released; after 12 hours, not less than 80% of Galantamine hydrobromide is released at pH 6.5 Phosphate buffer using USP Type II apparatus at 50 revolutions per minute.

In one aspect, the present invention provides controlled release pharmaceutical compositions of Galantamine comprising a plurality of matrix mini tablets; said compositions having atleast one or more of the following characteristics:

(a) said composition is characterized by the absence of release rate modifying coating;

(b) said composition is characterized by the absence of an immediate release

portion of the active ingredient Galantamine;

(c) said composition exhibits a dissolution profile such that up to 2 hours, not more than 60% of Galantamine hydrobromide is released; after 4 hours, about 50% to 80%) of Galantamine hydrobromide is released; after 12 hours, not less than 80% of Galantamine hydrobromide is released at pH 6.5 Phosphate buffer using USP Type II apparatus at 50 revolutions per minute.

In another aspect, the invention provides a process for preparation of matrix mini- tablet, said process comprising granulating Galantamine or a pharmaceutically acceptable salt thereof with atleast one release modifying agent to form a granulate mass; characterized in that the granulation of the mixture is carried out by hot melt granulation at a temperature of 40°C to 120°C.

In another aspect, the invention provides a process for preparation of controlled release compositions of Galantamine, said process comprising:

(a) preparing the matrix mini tablets; wherein the matrix mini tablets are prepared by the process comprising:

(i) providing a matrix core comprising Galantamine or a pharmaceutically acceptable salt thereof and one or more rate controlling polymers;

(ii) optionally coating the matrix core with a non-functional coating.

(b) filling the matrix mini tablets equivalent to the desired weight of active ingredient in to capsule shell.

In a preferred aspect, the invention provides a process for preparation of controlled release composition of Galantamine, said process comprising:

(i) providing a mixture of Galantamine or a pharmaceutically acceptable salt thereof, at least one diluent and optionally one or more release modifying agent to form a blend;

(ii) granulating Galantamine or a pharmaceutically acceptable salt thereof with atleast one water insoluble release modifying agent by hot melt granulation or by extrusion to form a granulate mass;

(iii) granulating the mass with an aqueous or organic solution of binder, drying and converting the mass into granules by milling and sizing;

(iv) optionally mixing the granules with one or more release modifying agent;

(v) optionally mixing the granules with one or more diluent(s), dry binder(s) and anti-adherent(s); (vi) lubricating the granules and compressing it into mini-tablets;

(vii) optionally coating the mini-tablets with non-release modifying coating agents;

(viii) filling the mini-tablets into capsule shell.

Additional aspects and/or advantages of the present invention will be evident from the description that follows.

Description of the invention:

The present invention provides controlled release pharmaceutical compositions of Galantamine comprising a plurality of mini tablets. Said compositions are useful for the treatment of mild to moderately severe dementia of Alzheimer type.

Preferably, the mini tablet is in the form of matrix mini tablet, which may optionally have a non-functional coating. Preferably, each discrete unit may optionally be coated with non-release modifying coat for physical appearance and/or to protect from moisture ingress in to the composition on stability.

According to one embodiment, the present invention provides controlled release compositions comprising the active ingredient Galantamine or a pharmaceutically acceptable salt thereof and at least one release modifying agent; wherein said composition comprises a plurality of matrix mini tablets. Preferably, the pharmaceutically acceptable salt is hydrobromide.

According to one embodiment, the present invention provides controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets, each comprising the active ingredient and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each matrix mini tablet comprises:

(a) Galantamine or a pharmaceutically acceptable salt thereof and (b) at least one of the release modifying agents selected from:

(i) one or more water soluble materials;

(ii) pne or more water insoluble materials or

(iii) one or more water swellable materials.

According to a preferred embodiment, the invention provides controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets, each comprising the active ingredient and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each matrix mini tablet comprises:

(a) Galantamine hydrobromide and

(b) at least one of the release modifying agents selected from:

(i) one or more water soluble materials;

(ii) one or more water insoluble materials or

(iii) one or more water swellable materials.

According to one embodiment, the present invention provides controlled release pharmaceutical compositions of Galantamine, wherein said composition is characterized by the absence of release rate modifying coating. Preferably, said compositions are characterized by the absence of a rate controlling polymer in the coat of the mini-tablet/pellet.

According to one embodiment, the invention provides controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets with optionally a non-functional coat and each comprising the active ingredient and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty capsule shell, wherein each matrix mini tablet is characterized by the absence of release rate modifying coating and comprises:

(a) Galantamine or a pharmaceutically acceptable salt thereof and

(ii) one or more water insoluble materials or

(iii) one or more water swellable materials.

According to another embodiment, the present invention provides controlled release pharmaceutical compositions of Galantamine, wherein said composition is characterized by the absence of an immediate release portion of the active ingredient Galantamine.

According to a preferred embodiment, the invention provides controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets with optionally a non-functional coat and each comprising the active ingredient and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty capsule shell, wherein each matrix mini tablet is characterized by the absence of release rate modifying coating and comprises:

(a) Galantamine hydrobromide and

(b) at least one of the release modifying agents selected from:

(i) one or more water soluble materials;

(ii) one or more water insoluble materials; or

(iii) one or more water swellable materials;

wherein said composition is characterized by the absence of an immediate release portion of the active ingredient Galantamine hydrobromide.

Preferably, said controlled release compositions are provided in the form of capsule dosage form having no immediate release component of Galantamine hydrobromide. In said controlled release dosage form, the pharmaceutically active agent or the therapeutically active agent is released according to a desired profile over an extended period of time. According to one embodiment, the controlled release pharmaceutical compositions of the present invention exhibit a dissolution profile such that up to 2 hours, not more than 60% of Galantamine hydrobromide is released; after 4 hours, about 50% to 80% of Galantamine hydrobromide is released; after 12 hours, not less than 80% of Galantamine hydrobromide is released at pH 6.5 Phosphate buffer using USP Type II apparatus ( paddle) at 50 rpm.

According to a preferred embodiment, the invention provides controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets, each comprising the active ingredient Galantamine and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each matrix mini tablet comprises:

(a) Galantamine or a pharmaceutically acceptable salt thereof and

(b) at least one of the release modifying agent selected from:

(i) one or more water soluble material;

(ii) one or more water insoluble material or

(iii) one or more water swellable material;

According to another preferred embodiment, the invention provides controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets, each comprising the active ingredient Galantamine and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each matrix mini tablet comprises:

(a) Galantamine or a pharmaceutically acceptable salt thereof and

(b) at least one of the release modifying agent selected from: (i) one or more water soluble material;

(ii) one or more water insoluble material or

(iii) one or more water swellable material;

According to one embodiment, the active ingredient is present in a micronized form. Galantamine or pharmaceutically acceptable salt, hydrate or solvate thereof is in the form of micronized particles; wherein said micronized particles have a D90 particle size of less than 100 micron. Preferably, the micronized particles have a D90 particle size of less than 50 micron and more preferably between 10 and 40 micron. In the practice of the present invention, the inventors have carefully done a selection of the particle size of the active ingredient so that an identical release profile with that of the innovator's clinically approved product is achieved.

According to one embodiment, the present invention provides controlled release pharmaceutical compositions of Galantamine comprising a plurality of matrix mini tablets; said compositions having atleast one or more of the following characteristics:

(b) said composition is characterized by the absence of an immediate release

portion of the active ingredient Galantamine;

(c) said composition exhibits a dissolution profile such that up to 2 hours, not more than 60% of Galantamine hydrobromide is released; after 4 hours, about 50% to 80% of Galantamine hydrobromide is released; after 12 hours, not less than 80% of Galantamine hydrobromide is released at pH 6.5 Phosphate buffer using USP Type II apparatus at 50 revolutions per minute.

According to one aspect of the invention, Galantamine is present in an amount from 2.0% to 20% by weight of the total composition; preferably in an amount from 5.0% to 15% by weight of the total composition.

According to another aspect of the invention, the ratio of Galantamine to release modifying agents is in the range of about 1 :1 to 1 :20; preferably 1 :2 to 1 : 15.

Mixtures of water soluble/water-swellable material with water-insoluble material may be employed in a weight ratio of about 10: 1 to 1 : 10, preferably 4: 1 to 1 :4.

According to one embodiment, the controlled release composition comprises of about 2% to about 25% by weight of Galantamine hydrobromide, about 30% to about 90% by weight of release modifying agent, about 10% to about 60% by weight of diluent, about 1% to about 10% by weight of binder, about 0.5% to about 5% by weight of lubricant, about 0.5% to about 5% by weight of glidant, about 2% to about 15% by weight of coating agents.

According to a preferred embodiment, the controlled release composition comprises about 5% to about 20% by weight of Galantamine hydrobromide, about 40% to about 70% by weight of release modifying agent, 10% to about 30% by weight of diluent, about 2% to about 10% by weight of binder, about 0.5% to about 5% by weight of lubricant, about 0.5% to about 5%by weight of glidant, about 2% to about 10% by weight of coating agents. In the practice of the present invention, matrix mini tablets equivalent to the desired weight of active ingredient is filled into the hard gelatin capsule or hard cellulose capsule. Empty hard gelatin capsule or empty hard cellulose capsules of size ranging from '4' to '0' may be used based on the desired weight of the formulation to be incorporated into the capsule dosage form.

In the practice of the present invention, the mini tablet may have a diameter from lmm to 3 mm and each capsule shell may contain a plurality of mini tablets ranging from 2 to 30. Tablets may be of various shape such as oval, elliptical, spherical or caplet shaped.

The controlled release compositions according to the present invention contain Galantamine in a dose range from 8mg to 24mg. Preferably, said compositions may contain Galantamine in doses such as 8mg, 16mg and 24mg. Said compositions are recommended for once-a-day administration in order to achieve a controlled effect of the drug. Controlled release compositions of present invention exhibit drug release profiles similar to marketed product Reminyl XL^®.

In the practice of the present invention, the release-modifying agents may be selected from one or more water-soluble materials and/or water-insoluble materials and/or water-swellable materials.

Water soluble materials which may be employed for the controlled release compositions include, but are not limited to polyethylene oxide (average molecular weight 1 ,00,000 to 50,00,000), sodium alginate, calcium ammonium alginate, potassium alginate, calcium alginate, celluloses such as hydroxypropyl methyl cellulose, propylene glycol alginate, polyvinyl alcohol, povidone, carbomers, xanthan gum, triethyl citrate, a co-polymer of vinylacetate and vinylpyrrolidone (Kollidon SR from BASF) and the like. Water-soluble materials may be present in an amount from 20% to 80% by weight of the total composition. Water insoluble materials which may be employed for the controlled release compositions include, but are not limited to stearic acid, glyceryl monostearate, glyceryl behenate, ethyl cellulose, glyceryl palmitostearate, microcrystalline wax, polymethacrylate, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydrogenated castor oil, polyvinyl acetate phthalate, waxes, shellac, tristearin, rosin, polyvinyl chloride powder or polyethylene powder, magnesium or aluminium silicates and the like and may be present in an amount from 20% to 80% by weight of the total composition.

Water-swellable materials which may be employed for the controlled release compositions include, but are not limited to alginic acid, guar gum and the like and may be present in an amount from 20% to 80% by weight of the total composition. The present invention further provides a process for preparation of controlled release compositions of Galantamine or a pharmaceutically acceptable salt thereof.

According to one embodiment, the process for preparation of controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets, each comprising the active ingredient Galantamine and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, said process comprising:

(i) preparing the matrix mini tablets; wherein the matrix mini tablets are prepared by the process comprising:

(a) providing a matrix core comprising Galantamine or a pharmaceutically acceptable salt thereof and one or more rate controlling polymers;

(b) optionally coating the matrix core with a non-functional coating.

(ii) ' filling the matrix mini tablets equivalent to the desired weight of active ingredient in to capsule shell.

According to a preferred embodiment, the process for preparation of controlled release pharmaceutical compositions comprising a plurality of matrix mini tablets, each comprising the active ingredient Galantamine and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, said process comprising:

(i) preparing the matrix mini tablets; wherein the matrix mini tablets are prepared ' by the process comprising:

(a) providing a matrix core comprising Galantamine hydrobromide and water insoluble material such as hydrogenated castor oil;

(b) optionally coating the matrix core with a non-functional coating.

(ii) filling the matrix mini tablets equivalent to the desired weight of active ingredient in to capsule shell.

According to one embodiment, the invention provides a process for preparation of Galantamine controlled release composition comprising granulating Galantamine hydrobromide with atleast one release modifying agent to form a granulate mass; characterized in that the granulation of the mixture is carried out by hot melt granulation at a temperature of 40°C to 120°C.

According to a preferred embodiment, the invention provides a process for preparation of mini-tablet, said process comprising granulating Galantamine or a pharmaceutically acceptable salt thereof with atleast one release modifying agent to form a granulate mass; characterized in that the granulation of the mixture is carried out by hot melt granulation at a temperature of 40°C to 120°C, sizing the granulate mass, blending the granules with pharmaceutically acceptable additives and compressing the blend into mini-tablets.

According to a more preferred embodiment, the invention provides a process for preparation of matrix mini-tablet, said process comprising granulating Galantamine or a pharmaceutically acceptable salt thereof with atleast one water insoluble material to form a granulate mass; characterized in that the granulation of the mixture is carried out by hot melt granulation at a temperature of 40°C to 120°C. According to another preferred embodiment, the process for preparation of controlled release compositions of Galantamine comprises:

(ii) granulating the blend of step (i) by hot melt granulation or by extrusion to form a granulate mass;

(iii) optionally granulating the mass of step (iii) with an aqueous or organic solution of binder and drying;

(iv) converting the mass of step(ii) or step(iii) into granules by milling and sizing;

(v) optionally mixing the granules with one or more release modifying agent, one or more diluent, binder or anti-adherants;

(vi) lubricating the granules and compressing it into mini-tablets;

(viii) filling the mini-tablets into capsule shell.

(i) preparing an intra-granular composition of Galantamine or a pharmaceutically acceptable salt thereof, at least one diluent and optionally one or more release modifying agent;

(ii) mixing the intra-granular composition with an extra-granular composition containing glidant, lubricant and optionally one or more release modifying agents to form a blend;

(iii) compressing the blend into mini-tablets;

(iv) optionally coating the mini-tablets; and (v) filling the mini-tablets into capsule shell.

According to a preferred embodiment, the process for preparation of Galantamine controlled release composition comprises the steps of:

(i) preparing an intra-granular composition by,

a) providing a mixture of Galantamine or a pharmaceutically acceptable salt thereof, at least one diluent and one or more release modifying agents to form a blend;

b) preparing a binder solution by dissolving the binder in a suitable solvent; c) granulating the blend of step (a) with binder solution of step (b) to form desired wet mass;

d) screening the wet mass of step(c) to form granules;

e) drying the granules of step (d) till loss on drying in the range of 0.5% to 5.0% is achieved;

f) sizing the dried granules of step (e).

(ii) mixing the intra-granular composition of step (i) with an extra-granular composition containing anti-adherents and optionally one or more release modifying agents to form a granule blend;

(iii) lubricating the granule blend of step (ii) with suitable lubricants;

(iv) compressing the lubricated granules of step (iii) into mini-tablets using suitable compression machine fitted with punches and dies;

(v) optionally coating the mini-tablets with non-release modifying coating agents,

(vi) filling the mini-tablets into suitable capsule shell.

In the practice of the present invention, the mini tablets may also be prepared by direct compression, slugging/deslugging, wet granulation or hot melt extrusion method.

The process for preparation of controlled release pharmaceutical compositions of Galantamine according to the present invention has the following advantages: (1) The process is easy and economical in comparison to prior art processes.

(2) The process involves reduced number of^* steps as compared to the prior art processes.

(3) The process involves less complex procedure as compared to the prior art processes.

The process for preparation of controlled release pharmaceutical compositions of Galantamine according to the present invention utilizes the technique that controls the release of Galantamine and significantly reduces the side effect, associated with conventional immediate release dosage forms. Said controlled release compositions of Galantamine can be given twice a day or more preferably can be given once a day. Said compositions demonstrate reliable release rate and facilitated in-vivo absorption for desired period of time.

According to another embodiment, the process for preparation of Galantamine controlled release composition comprises the steps of:

(1) providing a mixture of Galantamine or a pharmaceutically acceptable salt thereof, at least one diluent and one or more release modifying agents to form a blend;

(2) mixing the blend of step (1) with anti-adherents and finally lubricating the blend with suitable lubricants;

(3) compressing the lubricated granules of step (2) into mini-tablets using a compression machine fitted with suitable punches and dies;

(4) optionally coating the mini-tablets with non-release modifying coating agents;

(5) filling the mini-tablets into suitable capsule shell.

(i) providing a mixture of Galantamine or a pharmaceutically acceptable salt thereof, at least one diluent and one or more release modifying agents to form a blend;

(ii) preparing a binder solution by dissolving the binder in a suitable solvent;

(iii) granulating the blend of step (i) with binder solution of step (ii) to form desired wet mass;

(iv) screening the wet mass of step (iii) through extrusion of suitable sized screen to get extrudes of desire strength;

(v) optionally subjecting the extrudes of step (iv) to spheronization using suitable friction plates combination to get desired size distribution of particles;

(vi) drying the above particles or spheres of step (v) till loss on drying in the range of 0.5% to 5.0% is achieved;

(vii) selecting the desired size distribution of particles or spheres and fill them in suitable size capsules.

According to one embodiment, there is provided a method for treating alzheimer's disease by administering the controlled release compositions comprising Galantamine or salt thereof to patients in need.

Suitable pharmaceutically acceptable additives that may be used for formulation include, but are not limited to, diluents/fillers, binders, glidants/anti-adherants, lubricants, non-release modifying/non-functional coating agents and the like.

Diluents that can be used as per the invention include, but are not limited to calcium hydrogen phosphate, tribasic calcium phosphate, calcium carbonate, lactose, microcrystalline cellulose, magnesium carbonate, magnesium oxide or mixtures thereof and is present in an amount from about 10% to about 60% by weight of the total composition.

Binders that can be used as per the invention include, but are not limited to polyvinyl pyrrolidone, gelatin, polyvinyl alcohol, gum acacia and the like and is present in an amount from about 1.0% to about 15% by weight of the total composition.

Solvents that can be used as per the invention, include, isopropyl alcohol, methylene chloride, water or mixtures thereof in an amount sufficient to dissolve the binder.

Anti-adherents that can be used as per the invention include, but are not limited to colloidal silicon dioxide, talc, starch and the like and is present in an amount up to 3.0% by weight of the total composition.

Lubricants that can be used as per the invention include, but are not limited to magnesium stearate, calcium stearate, zinc stearate and the like and is present in an amount up to 3.0% by weight of the total composition.

Controlled release compositions, particularly the mini-tablets/pellets prepared by the process as described herein may be further film coated using non-functional coating composition employing any of the conventional coating techniques like pan coating, spray coating etc. Tablet coat of 2-10% with respect to total weight can be employed to make mini tablets aesthetically pleasing and allow the smooth flow from capsule filling machine.

Non-functional film coating may be carried out using one or more additives selected from the group comprising film formers, opacifiers, coating agents, taste-masking agents, colouring agents, antitacking agents and the like. Film formers such as hydroxypropyl cellulose or hydroxypropyl methyl celluloses or the like can be used. Opacifying agents that can be used include titanium dioxide, ferric oxide, sunset yellow and the like. Plasticizers such as polyethylene derivatives, polyethylene glycol, propylene glycol, triethyl citrate and the like can be used. Antitacking agents include talc, stearic acid, magnesium stearate, colloidal silicon dioxide and the like. Additives for non functional film coating can be used in concentrations which are well known to a person skilled in the art. Non-functional coating may also be carried out using readymade coating composition available as Opadry, Kollicoat (Graft copolymer of polyvinyl alcohol-polyethylene glycol) and the like. Non-functional film coating serves the purpose of taste neutralization, moisture protection and provides elegance to the mini tablets. Granulation may be carried out using high shear mixer or by spray granulation technique. Mixing and granulation can be carried out in a conventional rapid mixer granulator and the wet granules can be further dried using fluid bed drier. High shear granulation improves the cohesiveness of particles and provides excellent flowability and compression characteristics to the tablet. As the granules exhibit good flow properties, mini tablets produced possess uniformity in weight.

In the practice of the present invention, aqueous/non-aqueous granulation is carried out by adding the binder slowly in a thin stream continuously using a peristaltic pump under high speed mixing with the impeller 'on' and chopper Off'. On completion of binder addition, mixing is continued at high impeller speed till cohesive granular mass is obtained. If the mass is lumpy then chopper may be used at high speed with impeller also at high speed to obtain uniform wet mass. Drying of granulated mass may be carried out using fluidized bed drier or tray drier. Granulated mass is dried for sufficient time till loss on drying value in the range of about 0.5% to about 3.0% is achieved. In a conventional fluid bed processor both the steps of granulation and drying can be carried out in the same equipment thereby simplifying the process and saving the processing time. Compression may be carried out using equipments known in the art such as a rotary tablet press or any suitable tabletting machine fitted with suitable size punches and dies. Coating may be carried out using equipments known in the art such as spray coating or coating in conventional coating pan or perforated pans.

Compositions prepared by the process as described herein withstand the accelerated stability conditions of temperature and relative humidity and maintain their physical and chemical integrity at accelerated conditions of stability.

Controlled release pharmaceutical composition of Galantamine provides the following advantages over the immediate release oral pharmaceutical form,

i. Improved patient compliance to dosage regimens through the decrease in the number of doses the patient has to take in a day, by providing desired effective plasma levels.

ii. Decreased peak plasma levels when associated with side effects.

iii. Reduced side effects in chronic therapy by reducing the fluctuation in plasma levels seen after multiple dosing of conventional release systems.

Controlled release compositions prepared according to the present invention shows the following in-vitro drug release characteristics when tested in pH 6.5 phosphate buffer for the 1, 4 and 12 hours.

As used herein, the term "controlled release" refers to the release of the active ingredient according to a desired profile over an extended period of time.

As used herein, the term "additives" refers to a pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical technology for preparing granules and/or solid oral pharmaceutical dosage forms.

As used herein, the term "mini-tablet" is intended to encompass compressed pharmaceutical formulat ions of all shapes, whether coated or uncoated.

The present invention is further illustrated by reference to the following examples, which does not limit the scope of the invention in any way. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be practiced without departing from the purpose and scope of the disclosure. Examples:

Example 1

Galantamine hydrobromide (20.5 g), calcium hydrogen phosphate dihydrate (21.5g), microcrystalline cellulose [Avicel PH 102] (4.0 g), carbomer [Carbopol 71G] (60 g) and polyethylene oxide [Polyox WSR N 303] were sifted and mixed. The mixed blend was lubricated with magnesium stearate (2.0 g) and compressed into mini-tablets of size 1 to 3 mm. Compressed mini-tablets were coated by dispersing opadry (HPMC based) in non-aqueous vehicles to get uniform surface for controlled release mini tablets. Tablets were coated till a weight gain of about 1-10% was achieved. Finally the mini-tablets were filled in required size capsules.

Example 2

Galantamine hydrobromide (38.52g), lactose monohydrate (236.48g), microcrystalline cellulose (105 g), and polymethacrylate [Eudragit RLPO] (100.0 g) were mixed and granulated using binder solution containing hydroxypropyl cellulose (20.0 g) dissolved in purified water (180.0 g). The resultant mass was extruded and spheronised and the spherical particles were dried using rapid dryer. The dried particles were coated with non-functional coating agent and filled into capsules of required size.

Example 3

Stearic acid (71.19 g) was melted at 60°C. Galantamine hydrobromide (30.81 g) was heated to 60°C in a jacketed rapid mixer granulator and granulated with the melted stearic acid at 60°C. After granulation the mass was mixed continuously till it cools to room temperature and dry mass was milled to required size. Sized granules were blended with ollidOn SR (55.16 g) (Kollidon SR is a co-polymer of polyvinyl acetate and polyvinyl pyrrolidone), microcrystalline cellulose [Avicel PH 102] (1.45 g) and magnesium stearate (1.45 g). Compressed the blended granules into mini- tablets of size 1 to 3 mm. Compressed mini-tablets were coated with non- functional coating agent and filled into capsules of required size. Example 4

Stearic acid (95.19 g) was melted at 60°C. Galantamine hydrobromide (30.81 g) was heated to 60°C in a jacketed rapid mixer granulator and granulated with the melted stearic acid at 60°C. After granulation the mass was mixed continuously till it cools to room temperature and dry mass was milled to required size. Xanthan gum (98.98 g) was separately granulated with binder solution of povidone (2.95g) in isopropyl alcohol (30.0ml). The wet mass was dried till the desired loss on drying value was achieved. The dried Galantamine granules were mixed with the Xanthan gum granules and further lubricated with magnesium stearate (1.44g). Compressed the blended granules into mini-tablets of size 1 to 3 mm. Compressed mini-tablets were coated with non-functional coating agent and filled into capsules of required size.

Example 5

Stearic acid (47.46 g) was melted at 60°C. Galantamine hydrobromide (20.54 g) was heated to 60°C in a jacketed rapid mixer granulator and granulated with the melted stearic acid at 60°C. After granulation the mass was mixed continuously till it cools to room temperature and dry mass was milled to required size. Sized granules were blended with dicalcium phosphate (1 1.74 g), sodium alginate (107.57 g) and magnesium stearate (1 .96 g). Compressed the blended granules into mini-tablets of size 1 to 3 mm. Compressed mini-tablets were coated with non-functional coating agent and filled into capsules of required size.

Example 6

Galantamine hydrobromide (30.81 g), microcrystalline cellulose [Avicel PH 101] (83.19 g), and hypromellose [Methocel K100M] (120.0 g) were mixed and granulated using binder solution containing stearic acid (15.0 g) dissolved in isopropyl alcohol (81.9 g). The resultant mass was dried to get loss on drying value between 0.5-3.0%. The dried mass was mixed with Kollidon SR (57.0 g), talc (1.5 g) and magnesium stearate (1.5 g) in a blender and compressed into mini-tablets of size 1 to 3 mm. Compressed mini-tablets were coated with non-functional coating agent and filled into capsules of required size. Example 7

Hydrogenated castor oil (98.75g) was melted at 85°C. Galantamine hydrobromide (51.31g), microcrystaliine cellulose (69.94g), and ethyl cellulose (130.00g) was heated to 85°C in a jacketed rapid mixer granulator and granulated with the melted hydrogenated castor oil at 85°C and further mixed continuously till it cools to room temperature and the solidified mass was milled to granules of required size and further lubricated with magnesium stearate (lO.OOg). Compressed the blended granules into mini-tablets of size 1 to 3 mm. Compressed mini-tablets were coated with a non functional coat of Kollidon IR and the mini-tablets were filled into hard gelatin capsules of required size.

In- vitro dissolution study:

Table 1 summarizes the in-vitro dissolution profile for the controlled release Galantamine hydrobromide capsules prepared according to Example 7 of the present invention versus Reminyl XL^® (Innovator's Galantamine hydrobromide prolonged release capsules). Dissolution was carried out in phosphate buffer pH 6.5 using USP Type II (paddle), at 50 rpm.

Table 1

Bioequivalence study:

A single-dose crossover in vivo study was conducted on healthy, adult, human subjects under fasting and fed conditions. In vivo bioequivalence study for controlled release Galantamine hydrobromide capsules prepared according to Example 7 with respect to the Reminyl XL^® (Innovator's Galantamine hydrobromide prolonged release capsules) was conducted on 15 healthy subjects under fasting and fed conditions. The parameters C,„_ax, AUC₀-_t , AUCo-in_f that were estimated during the study are recorded in Table 2.

AUCo-t = Area under the plasma concentration versus time curve, from time zero to the last measurable concentration.

AUCo-inf = Area under the plasma concentration versus time curve, from time zero to infinity.

Cmax ⁼ maximum plasma concentration.

Table 2

Controlled release Galantamine hydrobromide capsules prepared according to Example 7 is bio-equivalent to reference product (Reminyl XL^®) when tested in-vivo on healthy, adult, human subjects under fasting and fed conditions. Stability study:

Controlled release compositions of Galantamine hydrobromide prepared according to Example 7 were subjected to stability studies at 40°C and 75% relative humidity (RH) for 6 months. Table 3 shows the results of Stability study.

Table 3

Example 8

Hydrogenated castor oil (59.00g) and stearic acid (20.00g) was melted at 85°C. Galantamine hydrobromide (41.07g), microcrystaliine cellulose (55.93g), and ethyl cellulose (104. OOg) was heated to 85°C in a jacketed rapid mixer granulator and granulated with the mixture of molten hydrogenated castor oil and stearic acid at 85°C and further mixed continuously till it cools to room temperature and the solidified mass was milled to granules of required size and further lubricated with magnesium stearate (8. OOg). Compressed the blended granules into mini-tablets of size 1 to 3 mm. Compressed mini-tablets were filled into hard gelatin capsules of required size.

In-vitro dissolution study

Table 4 summarizes the invitro-dissolution profile for the controlled release Galantamine hydrobromide capsules prepared according to Example 8 of the present invention versus Reminyl XL^® (Innovator's Galantamine hydrobromide prolonged release capsules). Dissolution was carried out in phosphate buffer pH 6.5 using USP Type II (paddle), at 50 rpm. Table 4

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

We claim,

1. A controlled release pharmaceutical composition comprising a plurality of matrix mini tablets, each comprising the active ingredient Galantamine and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each matrix mini tablet comprises:

(a) Galantamine or a pharmaceutically acceptable salt thereof and

(b) at least one of the release modifying agent selected from:

(i) one or more water soluble material;

(ii) one or more water insoluble material or

(iii) one or more water swellable material.

2. The composition as claimed in claim 1, wherein the composition is characterized by the absence of release rate modifying coating.

3. The composition as claimed in claim 1, wherein the composition is characterized by the absence of an immediate release portion of the active ingredient Galantamine.

4. The composition as claimed in claim 1, wherein Galantamine is present in an amount from 2.0% to 20% by weight of the total composition.

5. The composition as claimed in claim 1, wherein the pharmaceutically acceptable salt is a hydrobromide salt.

6. The composition as claimed in claim 5, wherein the hydrobromide salt of Galantamine is in micronized form having D90 less than 100 micron.

7. The composition as claimed in claim 1, wherein the ratio of Galantamine to the release modifying agent is from about 1 : 1 to about 1 :20; preferably from about 1 :2 to about 1 : 15.

8. The composition as claimed in claim 1, wherein the composition comprises from about 20% to about 80% by weight of the release modifying agent.

9. The composition as claimed in claim 8, wherein the release modifying agent comprises of water soluble material and/or water insoluble material and/or water swellable material.

10. The composition as claimed in claim 1, wherein said composition exhibits a dissolution profile such that up to 2 hours, not more than 60% of Galantamine hydrobromide is released; after 4 hours, about 50% to 80% of Galantamine hydrobromide is released; after 12 hours, not less than 80% of Galantamine hydrobromide is released at pH 6.5 Phosphate buffer using USP Type II apparatus at 50 revolutions per minute.

11. A controlled release pharmaceutical composition comprising a plurality of matrix mini tablets, each comprising the active ingredient Galantamine and pharmaceutically acceptable additives and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each matrix mini tablet comprises:

(a) Galantamine or a pharmaceutically acceptable salt thereof and

(b) at least one of the release modifying agent selected from:

(i) one or more water soluble material;

(ii) one or more water insoluble material or

(iii) one or more water swellable material;

12. The composition as claimed in claim 1 or claim 11, wherein said mini-tablet is optionally coated.

13. The composition as claimed in claim 12, wherein said coating is a nonfunctional coat.

14. The composition as claimed in claim 12, wherein the diameter of mini-tablet is from 1 mm to 3 mm.

15. The composition as claimed in claim 12, wherein the mini-tablet is characterized by the absence of an immediate release portion of the^" active ingredient Galantamine.

16. The composition as claimed in claim 12, wherein the mini-tablet is prepared by the process comprising granulating Galantamine or a pharmaceutically acceptable salt thereof with atleast one release modifying agent to form a granulate mass; characterized in that the granulation of the mixture is carried out by hot melt granulation at a temperature of 40°C to 120°C, sizing the granulate mass and further blending with pharmaceutically acceptable additives and compressing the blend into mini-tablets.

17. The composition as claimed in claim 1 or claim 11, wherein the composition comprises pharmaceutically acceptable additives selected from diluents, binders, lubricants, glidants and coating agents.

18. A process for preparation of controlled release composition of Galantamine, comprising the steps of :

(i) providing a matrix core comprising Galantamine or a pharmaceutically acceptable salt thereof and one or more rate controlling polymers; (ii) optionally coating the matrix core with a non-functional coating, (b) filling the matrix mini tablets equivalent to the desired weight of active ingredient in to capsule shell.

19. A process for preparation of mini-tablet as defined in claim 1 or claim 1 1 comprising granulating Galantamine or a pharmaceutically acceptable salt thereof with atleast one release modifying agent to form a granulate mass; characterized in that the granulation of the mixture is carried out by hot melt granulation at a temperature of 40°C to 120°C, sizing the granulate mass, blending the granules with pharmaceutically acceptable additives and compressing the blend into mini-tablets.

20. A process for preparation of controlled release composition of Galantamine according to any of the preceding claims comprising:

(vi) lubricating the granules and compressing it into mini-tablets;

(viii) filling the mini-tablets into capsule shell.