Field of the invention

The present invention relates to extended release dosage form of Anti-Alzheimer's drug. More particularly, the present invention relates to extended release dosage forms of galantamine hydrobromide.

The present invention also relates to a process for the preparation of extended release dosage form of galantamine hydrobromide.

Background of the invention

Galantamine hydrobromide is a reversible, competitive acetyl cholinesterase inhibitor and is chemically known as (4aS, 6R, 8aS)-4a, 5,9,10,1 1,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol hydrobromide.

Galantamine hydrobromide is marketed under the trade name Razadyne ® as an oral tablet as well as solution and Razadyne ER® as an extended release capsule in the US and also available under the trade name Reminyl® in Europe for the treatment of mild to moderate dementia of the Alzheimer's type.

Galantamine has an affinity for nicotinic receptors but not for muscarinic receptors, and it is capable of passing the blood-brain barrier. It is seen that immediate release therapy of galantamine hydrobromide leads to undesired peaks in the plasma profiles of galantamine and a sharp decrease in concentration after about 6 to 8 hours. Moreover, these fluctuations ranging from high to low plasma concentrations are undesirable and may lead to side effects, such as nausea, vomiting or headaches and these side effects generally precipitate in high doses. So a typical therapy with galantamine starts with a lower dose for 3 - 4 weeks and the dose is gradually increased till maximum tolerable dosage is achieved. But in this case if treatment with galantamine is interrupted for several days or longer, the patient will need to start over again at the lowest dose, increasing the dose at 4-week intervals until the former dose is achieved.

To overcome the above disadvantages, an extended release formulation was prepared which can permit once a day dosing by maintaing a stable drug plasma concentration for an extended period of time. Several prior art references describe compositions that are suitable for extended release dosage form of galantamine hydrobromide.

Galantamine hydrobromide extended release capsule dosage form has been approved by FDA in April 2005 and is commercially available under the trade name Razadyne ER® in the United State. Razadyne ER® comprise gelatin, diethyl phthalate, ethylcellulose, hypromellose, polyethylene glycol, titanium dioxide and sugar sphere (sucrose and starch). In addition the 16mg capsule contains red ferric oxide and 24 mg capsule contains red and yellow ferric oxide.

Given below are patents/patents publications, which disclose controlled release dosage form of galantamine or its salts.

US 7,160,559, US 2006/0062856 and US 2006/0093671 disclose a controlled release formulation comprising galantamine hydrobromide and a water soluble film forming polymer wherein the galantamine hydrobromide and the water soluble film forming polymer are layered or coated on inert spheres, said particles further coated by a release rate controlling membrane coating comprising water insoluble polymer and optionally a plasticizer, and the formulation further comprises a topcoat comprising galantamine and water-soluble polymer and wherein the formulation is capable of releasing 20 to 40% of the total amount of galantamine hydrobromide in 1 hour, and more than 80% of the total amount of galantamine hydrobromide in 10 hours.

US 2004/0097484 discloses a once a day pharmaceutical composition comprising galantamine and a pharmaceutically acceptable carrier, wherein the carrier comprising at least one gelling agent selected from water soluble organic gums, natural clays, synthetic clays and mixtures thereof, wherein the composition is prepared either by wet granulation or direct compression.

US 2005/0191349 discloses a sustained-release formulation comprising galantamine and a release-retarding material, wherein the release-retarding material comprising acrylate polymer, wax, modified cellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil or combinations thereof, wherein the formulation exhibits a dissolution profile such that less than about 18% of the galantamine is released in 1 hour, and less than about 80% of the galantamine is released in 10 hours.

US 2007/0092568 discloses a pharmaceutical composition comprising galantamine, a portion of the contained galantamine being present in an immediate release form and another portion being present in an extended release form, wherein immediate release form comprises inert particle coated with galantamine along with water insoluble component and extended release form comprises an inert particles coated with galantamine and water insoluble component and further coated with rate controlling substance.

US 2009/0087488 discloses a controlled release dosage form of galantamine comprising a core comprising galantamine and water insoluble excipients and a rate controlling coating wherein the rate controlling coating comprising one or more water insoluble polymers, a water soluble polymer and one or more plastisizer. This patent publication further discloses the core may include an inert sphere onto which one or more water insoluble excipients are coated having galantamine dispersed in it.

US 2009/0169617 discloses a controlled-release formulation comprising one or more distinct and discrete units located in physical juxtaposition to enable administration to a patient in a single dose, where each unit comprises (i) a unit dose of an active pharmaceutical ingredient or pharmaceutically acceptable salt thereof; (ii) one or more extended-release agent comprising a matrix of polymer and optionally (iii) one or more pharmaceutically acceptable excipients, wherein the

sum of the unit dose(s) constitutes a pharmaceutically effective amount of the active pharmaceutical ingredient.

US 2009/0254131 discloses a controlled release dosage form having a core comprising galantamine and water insoluble polymer and a release rate-controlling coating having release rate retarding excipients and the formulation further comprises immediate release top coat comprising galantamine and other polymer. The patent publication further discloses the core may comprises a core substrate of microcrystalline cellulose and a core coating layer comprising galantamine along with ethyl cellulose as binder and dibutyl sebacate as plasticizer.

WO 2005/099674 discloses sustained release composition of galantamine using starch sodium octenyl succinate as a release-retarding agent.

WO 2008/062426 discloses a controlled relesae formulation in the form of a hard gelatin capsule comrising a) functional coated composition of galantamine mainly comprising functional coat of surelease and b) an uncoated or seal coated composition of galantamine.

WO 2008/064734 discloses a controlled release composition comprising a pellet having an inert core, a first coating that is applied to the inert core and a second coating that is applied to the first coating wherein the first coating and the second coating contain galantamine or a pharmaceutically acceptable salt or solvent thereof and further the composition of the first coating is different from the second coating in having at least a film-forming or water insoluble polymer in one of the coating.

WO 2008/095263 discloses a dosage form comprising two or more active pharmaceutical ingredients wherein the first composition comprising a first active ingredient and optionally one or more excipients in a first physical form selected from the group consisting of powder, granule, pellet, bead or mini-tablet form, and at least a second composition comprising a second active ingredient and optionally one or more excipients in a second physical form selected from the group consisting

of granule, pellet, bead, mini-tablet or tablet form, wherein the composition is characterised in that said first and second physical forms are selected to be different to minimise interactions between said first and second pharmaceutical compositions and to allow separation of said first and second pharmaceutical compositions for analysis on the basis of size difference. This patent publication discloses various drugs including galantamine.

WO2009/076754 discloses a controlled release dosage form of galantamine comprising an inert core and a coating layer disposed over the inert core comprising a release controlling polymeric matrix in which an active pharmaceutical agent is distributed therein.

EP 2 044 933 discloses multi particulate matrix system (MPMS) comprising at least one type of particles, which contains galantamine that provides for prolonged release of active substance, and all particles present in the MPMS are uncoated. This patent publication further discloses multi particulate matrix system, wherein the particles are in the form of micro or mini tablets having a diameter of 1 mm to 5 mm.

The above prior art references disclose various extended release dosage form of galantamine hydrobromide. However, still there is a need for preparing extended release dosage form of galantamine hydrobromide, which is simple and cost effective. The inventors of the present invention during their continuous effort to develop extended release dosage form found that an inert core coated with a first coating layer containing galantamine without any water soluble or insoluble excipients and a second coating layer containing release rate controlling polymer, which is further coated with drug layer, releases the drug in a controlled manner and at the same time bioequivalent to the marketed dosage form.

Objective of the invention

Accordingly, the main objective of the present invention is to provide extended release dosage form of galantamine hydrobromide.

Yet another objective of the present invention is to provide extended release dosage form of galantamine in such a way that it will comply with the reference product in terms of in vivo parameters like bioequivalence and in vitro parameters like dissolution, disintegration etc.

Yet another objective of the present invention is to provide process for the preparation of extended release dosage form of galantamine hydrobromide.

Summary of the invention Accordingly, the main embodiment of the present invention is to provide extended release dosage form comprising: i. an inert core, ii. a first coating layer over the core containing galantamine hydrobromide
wherein the coating is free of excipients, iii. a second coating layer comprising release rate controlling polymer and one or more pharmaceutical acceptable excipients over the drug coated core and iv. finally an immediate release drug layer surrounding the second coating containing galantamine hydrobromide, wherein the immediate release layer is free of excipients.

Detailed description of the invention The inert core may include sugar pellets (non-pareil seeds), pellets, spheroids, tablets, mini tablets and the like. Pellets comprise microcrystalline cellulose (Ethispheres®, Celphere®), dicalcium phosphate or colloidal silicon dioxide.

Yet in another embodiment, when the core is in the form of a mini-tablet, comprises one or more excipients such as diluents selected from lactose, sucrose, dextrose, mannitol, starch, microcrystalline cellulose, dibasic calcium phosphate and the like or a combination thereof; binders selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelatin, alginates, starch, povidone,

copolyvidone, microcrystalline cellulose, pregelatinized starch and the like or a combination thereof; lubricants selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid and the like or a combination thereof and glidants selected from talc, sodium lauryl sulfate, colloidal silicon dioxide and the like or a combination thereof.

Yet in another embodiment, the core may comprises organic or inorganic acids such as hydrochloric acid, citric acid, nitric acid, tartaric acid and succinic acid.

In an embodiment of the present invention, the core further coated with first coating layer containing galantamine hydrobromide, which is free of any water-soluble or water insoluble excipients. The galantamine hydrobromide present in the first coating may be in the range of about 1-10%w/w.

In an embodiment of the present invention, the second coating layer comprises release rate controlling polymer selected from the group containing ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl acetate, polyvinyl alcohol, carbopol, copolymers of methacrylic acids or its ester, alginic acid or its salts, xanthan gum, polyethylene oxide and the like or a combination thereof. The release rate-controlling polymer used may be in the range of about 1-15% w/w.

Yet in another embodiment, the second coating layer further comprises plasticizers and hydrophilic pore forming agents.

Suitable plasticizers used according to the present invention are selected from triacetin, polyethylene glycol, diethyl phthalate, triethyl citrate and the like or a combination thereof.

Suitable hydrophilic pore forming agents used according to the present invention are selected from hydroxy propyl methylcellulose, hydroxy propyl cellulose and the like or a combination thereof.

Yet in another embodiment, the coated core is further coated with an immediate release drug layer containing galantamine hydrobromide, which is free of any water-soluble or water insoluble excipients. The amount of galantamine used in the immediate release drug layer may be in the range of about 1-10% w/w.

The immediate release coated core may optionally coated with film coating composition. The coating solution mainly comprises film forming polymers and one or more of plasticizers, opacifier, surfactant, anti tacking agents, coloring agent and the like.

Yet in another embodiment, dosage form of the present invention may be in the form of tablets, minitablets or pellets filled in the capsule and each capsule comprising of about 4-7 minitablets.

The coating is applied by dissolving / dispersing the excipients in solvents such as isopropyl alcohol, water, acetone, ethanol, dichloro methane and the like or a combination thereof.

Yet in another embodiment, the ratio of galantamine present in first coating layer and immediate release coating layer, is in the range of about 4:1 to about 1:1.

Yet in another embodiment, the extended release dosage form of galantamine comprises:

i. an inert core, ii. a first coating layer over the core containing galantamine hydrobromide wherein the coating is free of excipients, iii. a second coating layer comprising release rate controlling polymer and one or more pharmaceutical acceptable excipients over the drug coated core and iv. finally an immediate release drug layer surrounding the second coating containing galantamine hydrobromide, wherein the immediate release layer is free of excipients, having the dissolution profile such as

1. not less than 10% of galantamine is released after 2 hour,
2. not less than 20% of galantamine is released after 4 hour,
3. not less than 40% of galantamine is released after 8 hour,
4. not less than 90% of galantamine is released after 12 hour.

In a preferred embodiment, the extended release dosage form comprises: i. an inert core in the form of mini tablets,

ii. a first coating layer over the core containing about 1 to 10% w/w of galantamine hydrobromide wherein the coating is free of excipients,

iii. a second coating layer comprising about 1 to 15% w/w of release rate controlling polymer selected from ethylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl acetate over the drug coated core and

iv. finally an immediate release drug layer surrounding the second coating containing about 1 to 10%w/w of galantamine hydrobromide, wherein the immediate release layer is free of excipients.

The present invention also provides a process for the preparation of an extended release dosage form comprising: i. an inert core, ii. a first coating layer over the core containing galantamine hydrobromide wherein the coating is free of excipients, iii. a second coating layer comprising release rate controlling polymer and one or more pharmaceutical acceptable excipients over the drug coated core and iv. finally an immediate release drug layer surrounding the second coating containing galantamine hydrobromide, wherein the immediate release layer is free of excipients, which comprises the following steps:

1) preparing a solution or suspension of galantamine hydrobromide by dissolving in suitable solvent,

2) applying the drug solution of step (1) onto the inert core to obtain a drug coated core,

3) preparing a coating solution by dissolving release rate controlling polymer and one or more pharmaceutical acceptable excipients in suitable solvent,

4) applying the coating solution of step (3) onto the drug coated core to obtain coated cores,

5) coating the cores of step (4) with the solution of an immediate release drug layer containing galantamine hydrobromide in suitable solvent and

6) optionally coating the coated core with film coating compositions and finally filled in the capsule.

In yet another embodiment, there is provided a method for the treatment of mild to moderate dementia of the Alzheimer's type, by administering extended release dosage form of galantamine hydrobromide of the present invention.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

Ingredients Qty / Mini tab (nig)
Inert Core

Microcrystalline cellulose 22.78
Colloidal silicon dioxide 1.00
Povidone 1.05
Magnesium stearate 0.17
Drug Coating
Galantamine hydrobromide 1.54
Purified water q.s

Release Controlling Coating
Ethylcellulose 0.93
Diethyl phthalate 0.27
Hydroxy propylmethyl cellulose 0.13
Ethanol q.s
Dichloromethane q.s
Immediate release drug layer
Galantamine HBr 0.51
Purified water q.s
Film Coat
Opadry 1.02

The processing steps involved in manufacturing extended release capsule dosage form of galantamine hydrobromide as described in example 1 are given below:

i) microcrystalline cellulose, colloidal silicon dioxide and povidone were blended,

ii) lubricated the blend of step (i) with magnesium stearate,

iii) compressed the lubricated blend of step (ii) into mini-tablets,

iv) a solution of galantamine hydrobromide was prepared in purified water,

v) coated the solution of step (iv) onto the mini-tablets to form drug coated tablet,

vi) a solution of release controlling coating was prepared by dissolving
ethylcellulose, hydroxy propylmethyl cellulose and diethyl phthalate in a mixture of ethanol and dichloromethane and applied onto the drug coated tablets of step (v),

vii) an immediate release coating of galantamine was prepared by dissolving galantamine hydrobromide in water and applied on mini-tablet, obtained in step (vi) and

viii) finally the minitablets were coated with opadry film coating. Five minitablets equivalent to galantamine 8mg were filled in size 0 empty hard gelatin capsule shell.
The compositions given in example 2-4 were prepared using similar procedure as described in example 1.

Example 2

Ingredients Qty / Mini tab (mg)
Inert Core

Dibasic calcium phosphate dihydrate 23.760
Lactose monohydrate 15.840
Magnesium stearate 0.400
Drug Coating
Galantamine hydrobromide 1.795
Purified water q.s
Release Controlling Coating
Ethyl cellulose 1.560
Hypromellose 0.530
Diethylphathalate 0.430
Isopropyl alcohol q.s
Dichloromethane q.s
Immediate release drug layer
Galantamine HBr 0.768
Purified water q.s
Example 3

Ingredients Qty / Mini tab (mg)
Inert Core

Dibasic calcium phosphate dihydrate 23.760
Lactose monohydrate 15.840
Hydrochloric acid 0.005
Magnesium stearate 0.400
Drug Coating
Galantamine hydrobromide 1.795
Purified water q.s
Release Controlling Coating
Ethylcellulose 1.160
Hypromellose 0.420
Diethylphathalate 0.420
Isopropyl alcohol q.s
D ichlor omethane q.s
Immediate release drug layer
Galantamine HBr 0.769

Purified water

Example 4

Ingredients Qty / Mini tab (mg)
Inert Core

Mannitol 30.40
Dibasic calcium phosphate dihydrate 7.600
Hydrochloric acid 0.005
Povidone
Magnesium stearate 0.400
Drug Coating
Galantamine hydrobromide 1.795
Purified water q.s
Release Controlling Coating
Ethyl cellulose 1.530
Hypromellose 0.550
Diethylphathalate 0.550
Isopropyl alcohol q.s
Dichloromethane q.s
Immediate release drug layer
Galantamine HBr 0.769
Purified water q.s
Example 5

Ingredients Qty / pellet (mg)
Inert Core

Microcrystalline cellulose sphere 100.00
Drug Coating
Galantamine hydrobromide 7.69
Purified water q.s
Release Controlling Coating
Ethylcellulose 10.29
Diethyl phthalate 2.94
Hydroxy propylmethyl cellulose 1.47
Ethanol q.s
Dichloromethane q.s

Immediate release drug layer
Galantamine HBr 2.56
Purified water q.s
Film Coat
Opadry 5.05

The processing steps involved in manufacturing extended release capsule dosage form of galantamine hydrobromide as described in example 5 are given below:
i) a solution of galantamine was prepared by dissolving galantamine hydrobromide in water,
ii) a solution of step (i) was applied on the microcrystalline cellulose sphere to form drug-coated pellets,

iii) a solution of release controlling coating was prepared by dissolving
ethylcellulose, hydroxy propylmethyl cellulose and diethyl phthalate in a mixture of ethanol and dichloromethane and applied onto the drug coated pellets of step (ii),

iv) an immediate release coating of galantamine was prepared by dissolving galantamine hydrobromide in water and applied on coated pellets obtained in step
(iii) and
v) finally the pellets were coated with opadry film coating. 130mg pellets equivalent to 8 mg galantamine were filled into size 4 empty hard gelatin capsule shells.

The extended release dosage forms of galantamine hydrobromide prepared according to the present invention were tested for drug release in 900 ml media for 12 hours followed by phosphate buffer of pH 6.5 using USP apparatus 2 with paddle speed at 50 rpm. The samples of the media were periodically withdrawn and spectrophotometrically analyzed for galantamine content. The dissolution profile is given in Table 1.

Table-1

(%) Galantamine Release
Time (hr) Razadyne ER Capsule (8mg) Example 1 Example 2 Example 3 Example 4
1 30 30 26 30 29
2 44 51 40 37 37
3 55 66 53 43 48
4 64 74 64 50 60
6 76 81 78 65 76
8 84 87 87 78 84
10 89 89 92 88 89
12 93 90 94 93 91

We claim:

1. An extended release dosage form comprising:
i) an inert core,
ii) a first coating layer over the core containing galantamine hydrobromide
wherein the coating is free of excipients,
iii) a second coating layer comprising release rate controlling polymer and one or more pharmaceutical acceptable excipients over the drug coated core and
iv) finally an immediate release drug layer surrounding the second coating containing galantamine hydrobromide, wherein the immediate release layer is free of excipients.

2. The dosage form as claimed in claim 1, wherein the release rate controlling polymer is selected from ethylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl acetate, polyvinyl alcohol, carbopol, copolymers of methacrylic acids or its ester, alginic acid or its salts, xanthan gum, polyethylene oxide or a combination thereof.

3. The dosage form as claimed in claim 1, the second coating layer further comprise plasticizer and hydrophilic pore forming agent.

4. The dosage form as claimed in claim 3, wherein the plastisizer is selected from triacetin, polyethylene glycol, diethyl phthalate, triethyl citrate or a combination thereof.

5. The dosage form as claimed in claim 3, wherein the hydrophilic pore forming agent is selected from hydroxy propyl methylcellulose, hydroxy propyl cellulose or a combination thereof.

6. The dosage form as claimed in claim 1, the ratio of galantamine present in first coating layer and immediate release coating layer is in the range of about 4:1 to about 1:1.

7. The dosage form as claimed in claim 1, wherein the core is in the form of a mini-tablet, comprises one or more excipients such as diluents selected from lactose, sucrose, dextrose, mannitol, starch, microcrystalline cellulose, dibasic calcium phosphate or a combination thereof; binders selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelatin, alginates, starch, povidone, copolyvidone, microcrystalline cellulose, pregelatinized starch or a combination thereof; lubricants selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid or a combination thereof and glidants selected from talc, sodium lauryl sulfate, colloidal silicon dioxide or a combination thereof.

8. An extended release dosage form, which comprises:
i) an inert core,
ii) a first coating layer over the core containing galantamine hydrobromide
wherein the coating is free of excipients,
iii) a second coating layer comprising release rate controlling polymer and
one or more pharmaceutical acceptable excipients over the drug coated
core and
iv) finally an immediate release drug layer surrounding the second coating containing galantamine hydrobromide, wherein the immediate release layer is free of excipients, having the dissolution profile such as

1. not less than 10% of galantamine is released after 2 hour,
2. not less than 20% of galantamine is released after 4 hour,
3. not less than 40% of galantamine is released after 8 hour,
4. not less than 90% of galantamine is released after 12 hour.

9. An extended release dosage form, which comprises:

i) an inert core in the form of mini tablets,
ii) a first coating layer over the core containing about 1 to 10%w/w of galantamine hydrobromide wherein the coating is free of excipients,

iii) a second coating layer comprising about 1 to 15%w/w of release rate controlling polymer selected from ethylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl acetate over the drug coated core and

iv) finally an immediate release drug layer surrounding the second coating containing about 1 to 10%w/w of galantamine hydrobromide, wherein the immediate release layer is free of excipients.

10. A process for the preparation of an extended release dosage form comprising:

i) an inert core,

ii) a first coating layer over the core containing galantamine hydrobromide wherein the coating is free of excipients,

iii) a second coating layer comprising release rate controlling polymer and one or more pharmaceutical acceptable excipients over the drug coated core and

iv) finally an immediate release drug layer surrounding the second coating containing galantamine hydrobromide, wherein the immediate release layer is free of excipients, which comprises the following steps:

1) preparing a solution or suspension of galantamine hydrobromide by dissolving in suitable solvent,

2) applying the drug solution of step (1) onto the inert core to obtain a drug coated core,

3) preparing a coating solution by dissolving release rate controlling polymer and one or more pharmaceutical acceptable excipients in suitable solvent,

4) applying the coating solution of step (3) onto the drug coated core to obtain coated cores,

5) coating the cores of step (4) with the solution of an immediate release drug layer containing galantamine hydrobromide in suitable solvent and
6) optionally coating the coated core with film coating compositions and finally filled in the capsule.