FORM 2
THE PATENTS ACT. 1970
(39 of1970)
&
THE PATENTS RULES, 2003
Complete Specification [See Sections 10 and rule 13]
Title: Modified release pharmaceutical composition of Memantine
Applicant: (a) Astron Research Ltd
(b) Company Registered under Indian Company ACT
(c) 10th Floor, Premier House Bodakdev, Opp. Gurudvvara Sarkhej - Gandhinagar Highway
Ahmedabad 380054"" Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be preformed describes the invention:

FIELD OF THE INVENTION
This present invention relates to modified release pharmaceutical composition of memantine or its pharmaceutical!)' acceptable salts thereof and process for preparation of the same. The invention is particularly suitable for once-a-day solid oral pharmaceutical dosage forms, possessing improved formulation characteristics and release a therapeutically effective amount of the active ingredient over an extended time period.
BACKGROUND OF THE INVENTION
Memantine is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride is l-amino-3. 5-dimethyladamantane hydrochloride with the following structural formula:

Memantine HCI occurs as a fine white to off-white powder and is soluble in water. The molecular formula is CI2H21N.WC1 and the molecular weight is 215.76.
Memantine and other 1-aminoalkylcyclohexanes have proven useful in alleviation of various progressive neurodegenerative disorders such as dementia in patients with

moderate to severe AD, Parkinson's disease, and spasticity. Memantine is currently approved for the treatment of moderate to severe AD.
Currently, a dosing regimen of memantine twice a day is employed using immediate release tablets and once a day dosing regimen employed using sustained release tablets. Memantine immediate release tablet is marketed in US by Forest under trade name Namenda ® and in Europe by Merz under trade name Axura ® and Ebixa ®. It is available for oral administration as capsule shaped Film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride. The commercially available (approved by US FDA) extended release composition of memantine is Namenda XR capsules.
In the prior art, many techniques have been used to provide sustained and extended-release pharmaceutical compositions of memantine in order to maintain therapeutic levels of medicaments and to minimize the effects of missed doses of drugs caused by a lack of patient compliance. Some of sustained release compositions for memantine described in prior art are as follows:
US5382601 discloses solid pharmaceutical dosage forms containing memantine which exhibit an extended two-phase release profile, the matrix of this formulation contains both a water-soluble and a water-insoluble salt of casein, preferably sodium and calcium caseinate.
US6194000 disclose a method for the therapeutic treatment of pain related to wind up in a human or animal. The method of the invention is practiced by administering to the subject an effective amount of an analgesic pharmaceutical composition which includes a NMDA receptor antagonist in an immediate release form combined with an NMDA receptor antagonist in a sustained release form.

US20060051416 discloses once-a-day solid oral pharmaceutical dosage forms containing memantine or sail thereof and a pharmaceiitically acceptable polymeric carrier (coating and/or matrix) contributing to release a therapeutically effective amount of the active ingredient from about 4 hours to about 24 hours.
US201000266684 discloses solid pharmaceutical composition comprising an extended release form of memantine in pellet containing a capsule dosage form wherein the composition comprises coated cores having about 8%-16.5% by weight a sustained release coating comprising ethyl cellulose and a porosity enhancer selected from the group consisting of PVP and HPMC a plasticizer. and an ethyl cellulose to porosity enhancer ratio of about 8:2 to 9: 1.
WO2012101653 disclose the modified release pharmaceutical compositions of memantine or pharmaceutically acceptable salts thereof wherein the composition exhibits a biphasic release profile and the amount of the binder is more than 3% by weight of the composition.
WO2012110912 disclose the sustained release coating on a core comprising memantine or its pharmaceutically acceptable salts and one or more pharmaceutical acceptable excipient(s). Furthermore sustained release coating comprising a water insoluble substance and a water soluble substance, wherein ratio of the water insoluble substance to the water soluble substance is from about 1:0 to about 3.5: 1.
Memantine immediate release marketed formulations are mostly given twice daily, however switching to once daily sustained release formulation have possible benefits over memantine IR like improved patient compliance & control of symptoms due to less frequent dosing and may provide an improved side- effect profile.

Memantine or a pharmaceuticals acceptable salt thereof, is highly soluble in aqueous media and polar solvents. A drug of a high water-solubility can dissolve in water or gastrointestinal tract readily and tends to release from its dosage form in a burst and thus is absorbed quickly, leading to a sharp increase in the drug blood concentration. This leads to greater frequency of adverse pharmacological events due to the fast rate of absorption. It is very difficult to develop the modified release pharmaceutical composition having extended release properties which provide a sustained release of memantine or a pharmaceutically acceptable salt thereof over an extended period of time.
However, there is still an existing and continual need for a once a day modified release formulation containing memantine or it's a pharmaceuticals acceptable salt with reliable slower absorption over a targeted period of time. The inventors of the present invention address the need to provide once a day modified release pharmaceutical composition to overcome the above mentioned problems.
OBJECTS OF THE INVENTION
The object of the present invention is to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts,
Another object of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprises sustained release pellets.

Another object of the present invention is to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising:
(a) a core,
(b) optionally a seal coating layer around the core.
(c) one or more drug layer on to inert core comprising memantine or pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient(s),
(d) optionally a seal coating layer on drug coated core.
(e) sustained release coating on drug layer comprising at least one rate controlling polymer(s) and one or more pharmaceutically acceptable excipient(s),
(f) optionally seal coating layer on sustained release coating
Another object of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising about 40-80% of the core by weight of the total composition.
Another object of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising about 8-20% of memantine or its pharmaceutically acceptable salts by weight of total composition.
Another object of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising about 4-20% of rate controlling polymer by weight of the total composition.

Another object of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts wherein the seal coating comprising one or more pharmaceutically acceptable excipient(s).
Another object of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising sustained release pellets optionally with immediate release pellets.
Another object of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising optionally 2-10% immediate release pellets.
Another object of the present invention is to provide a process for the preparation of modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising:
(a) a core.
(b) optionally a seal coating layer around the core.
(c) one or more drug layer on to inert core comprising memantine or pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient(s).
(d) optionally a seal coating layer on drug coated core.
(e) sustained release coating on drug layer comprising at least one rate controlling polymer(s) and one or more pharmaceutically acceptable excipient(s).
(0 optionally seal coating layer on sustained release coating
Another object of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising

sustained release pellets optionally with immediate release pellets filled in hard gelatin capsules or compressed in tablets.
Another object of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts release a therapeutically effective amount of the memantine over an extended time period.
SUMMARY OF THE INVENTION
The present invention relates to a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts. The present invention provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising sustained release pellets optionally with immediate release pellets. The invention is particularly suitable for once-a-day solid oral pharmaceutical dosage forms and releases a therapeutically effective amount of the active ingredient over an extended time period.
DETAILED DESCRIPTION
Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.
The inventors of the present invention have surprisingly found that it is possible to develop a stable and multiple phase release formulation of memantine or salts thereof which are suitable for once daily administration release a therapeutically effective amount of the active ingredient over an extended time period.

Thus, the object of the present invention is to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts. Further the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising sustained release pellets.
In yet another embodiment of the present invention is to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising sustained release pellets comprising:
(a) a core,
(b) optionally a seal coating layer around the core.
(c) one or more drug layer on to inert core comprising memantine or pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient(s).
(d) optionally a seal coating layer on drug coated core.
(e) sustained release coating on drug layer comprising at least one rate
controlling polymer(s) and one or more pharmaceutically acceptable
excipient(s),
(f) optionally seal coating layer on sustained release coating
The term "modified release pharmaceutical composition" as used hereinbefore and throughout the description includes dosage forms containing combination of components providing immediate release and sustained release of memantine or salts thereof from the dosage form.
The term "sustained release" as used hereinbefore and throughout the description refers to drug delivery system releasing the drug at a predetermined rate, locally or systemically, for a specified period of time. Sustained release can be used

interchangeably with prolonged release, programmed release, timed release, extended release, controlled release, and modified release, slow release and other such dosage forms.
The term "memantine" used throughout the specification refers to not only memantine per se. but also its pharmaceutically acceptable salts, pharmaceutical!}' acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, ft is also possible to use any salts and free base form of memantine. including polymorphs, hydrates, solvates or amorphous forms. The preferred salt of memantine is hydrochloride salt.
In another embodiment of the present invention the amount of memantine or salt thereof in the modified release composition ranges from about 8% to about 20% by weight of the total composition.
The term "core" according to the invention an inert substance layered with memantine, optionally mixed with other pharmaceutically acceptable excipients, can be used as the core material for the further processing. The core can be homogenous or have an internal structure comprising pellets, tablets, minitablets, capsules, granules, beads or pills.
The term "inert" is a pharmaceutical substance which is inactive in relation to the active ingredient and other pharmaceutically acceptable excipient(s). that is to say. it does not react with the active ingredient and other pharmaceutically acceptable excipient(s) in the conditions used in such a way that there is decomposition thereof. The inert substance can be but not limited to different oxides, celluloses, organic

polymers, different inorganic salts, sugars, non-pareils. alone or in mixtures. Before the seeds are layered, the active substance may be mixed with one or more other pharmaceutically acceptable excipients.
In another embodiment of the present invention the amount of core in the modified release composition ranges from about 40% to about 80% by weight of the total composition.
The term "seal coat" is synonymous to various terms like separating layer, seal coating layer, intermediate layer, barrier coating layer, film coating and the like. Seal coat comprises the substances but not limited to water-soluble substance, water-insoluble substance and one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients dissolve in solvent & applied this solution on core as a seal coat.
In another embodiment of the invention there is an optionally seal coat between the core and the drug layer.
In another embodiment of the invention there is an optionally seal coat between the drug layer and sustained release coating. Finally the sustained release pellets of memantine optionally seal coated and compressed into tablets or filled in capsules.
In another embodiment of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising about 4-20% of rate controlling polymer by weight of the total composition. The rate controlling polymers are dissolved in solvents & coated on the drug coated pellets.

Suitable "rate controlling polymers" may include one or more of hydrophilic and hydrophobic polymers or mixtures thereof.
Suitable hydrophilic polymers may include one or more of cellulosic polymers/copolymers or its derivatives including methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose. sodium carboxymethylcellulose; polyethylene oxides, polyethylene glycols, chitosan. gums, starch derivatives, polyurethanes, polysaccharides, polyalcohols and the like. The preferred hydrophilic polymer is hydroxypropyl methylcellulose or any commercially available grade thereof.
Suitable hydrophobic polymers includes but not limited to cellulose derivatives as ethyl cellulose, ethyl cellulose aqueous dispersion, cellulose acetate, poly (alky!) methacrylate, copolymers of acrylic or methacrylic acid esters, polymethacrylates containing quaternary ammonium group, high molecular weight polyvinyl alcohols, polyvinyl acetate dispersion (eg: Kollidon). waxes, hydrogenated vegetable oil. fatty acids; long chain fatty alcohols, cellulose acetate butyrate or mixtures thereof and other materials known to one of ordinary skill in the art. The preferred hydrophobic polymer is ethyl cellulose.
in one preferred embodiment of the present invention the rate controlling layer comprises ethyl cellulose as hydrophilic polymer, povidone as hydrophobic polymer, polyethylene glycol as a plasticizer using isopropanol and methylene chloride as a solvent system.
The sustained release coating may further comprise one or more pharmaceuticaily acceptable excipients(s).

Pharmaceutically acceptable excipient(s) include but are not limited to binders, fillers or diluents, lubricants, glidants or solvent(s) and mixtures thereof. One excipient can perform more than one function. All excipienls can be used at levels well known to the persons skilled in the art may be selected from but are not limited to starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethy] cellulose, ethyl cellulose, sodium carboxy methyl cellulose;, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, carbohydrates, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol. mannitol. sucrose, lactose, calcium phosphate dibasic or tribasic, calcium sulphate. Mg. A! or Ca or Zn stearaie. glyceryl behenate, mineral oil. sodium stearyl fumarale. stearic acid, talc, silicon dioxide, magnesium trisilicate. powdered cellulose, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate and other materials known to one of ordinary skill in the art and combinations thereof.
Solvents may be used in present invention include all the solvents well known in the art or their mixtures thereof are selected from the group comprising methyl alcohol, ethyl alcohol, isopropanol, methylene chloride, acetone, acetonilrile, purified water, or mixture thereof.
In another embodiment of the present invention to provide a modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising sustained release pellets optionally with immediate release pellets.

In another embodiment of the invention modified release pharmaceutical composition comprising optionally 2-10% immediate release pellets.
In another embodiment of the invention the process for the preparation of modified release pharmaceutical composition of memantine or its pharmaceutical!}' acceptable salts comprising sustained release pellets comprising:
(a) a core.
(b) optionally a seal coating layer around the core,
(c) one or more drug layer applied to inert core comprising memantine or pharmaceutically acceptable salts with at least one pharmaceuticaliy acceptable excipient(s).
(d) optionally a seal coating layer on drug coated core.
(e) sustained release coating on drug layer comprising at least one rate controlling polymer(s) and one or more pharmaceutically acceptable excipient(s),
(0 optionally seal coating layer on sustained release coating.
In yet another embodiment of the invention pharmaceutical composition of the invention can be prepared by combining immediate release pellets of memantine with sustained release pellets of memantine and compressed into tablets or filled in capsules.
The composition of the present invention optionally includes memantine as immediate release part in association with a sustained release part. The composition may include an amount of memantine in the immediate release part of approximately 2% to 10% of the total memantine. The sustained release part of memantine may constitute the remainder of the active ingredients. The sustained release composition of memantine may have a single phase or multiphase release profile.

The composition of the invention is suitable for the treatment of mild to moderate and moderate to severe Alzheimer's disease, memory disorder, retention disorder, and cognitive subjective, cognitive impairment, memory, concentration or attention problems.
The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure, and the accompanying claims.
Example: 1

Ingredients %w/w
A. Base material
Inert core (40-80%)
B. Seal Coating (Optional)
Pharmaceutical excipients for seal coating (1-4%)
C. Drug Layering
Memantine HCI (8-20%)
Pharmaceutical excipients (2-10%)
D. Seal Coating (Optional)
Pharmaceutical excipients for seal coating (2-4%)
E. Sustained release coating
Water insoluble polymers (4-20%)
Water soluble polymers (0-4%)
Organic solvents Q.S.
F. Seal Coating (Optional)
Pharmaceutical excipients for seal coating (1-4%)
Total Weights 100%
Brief manufacturing process;
1. Optionally seal coat the inert core with seal coating pharmaceutical excipients.

2. Prepare the solution of Memantine HCI with pharmaceutical excipients in solvent.
3. Coat the drug solution of step 2 on optionally seal coated core of step I.
4. Optionally seal coated the above drug coated core with pharmaceutical excipients.
5. Prepare the sustained release coating solution with polymers and pharmaceutical excipients in solvent.
6. Coat the drug loaded core of step 3 with sustained release coating solution of step 5.
7. Optionally seal coated the above sustained release coating pellets and filled into capsule
Example: 2

Ingredients %w/w
A. Base materia]
Sugar Sphere / MCC Sphere (40-80%)
B. Seal Coating
Hydroxy propyl methyl cellulose/ polyvinyl pyrrolidone (1-4%)
Purified water Q.S.
C. Drug Layering
Memantine HCI (8-20%)
Hydroxy propyl methyl cellulose/ polyvinyl pyrrolidone (3-8%)
Talcum (0.5-2%)
Purified water Q.S.
D. Seal Coating
Hydroxy propyl methyl cellulose/polyvinylpyrrolidone (2-4%)
Purified water Q.S.
E. Sustained release coating
Ethyl cellulose aqueous dispersion / Ethyl cellulose / Eudragit RL&RS/Kollidone SR (4-20%)
Hydroxy propyl methyl cellulose (0-4%)
Purified water Q.S.
Isopropanol Q.S.
Dichloromethane Q.S.

F. Seal Coating
Hydroxypropyl methyl cellulose/polyvinylpyrrolidone (1-4%)
Purified water Q.S.
Total Weights 100%
Brief manufacturing Process:
J. Sea! coat the base material (sugar sphere/MCC) with hydroxypropyl methyl cellulose OR poly vinyl pyrrolidone solution in water.
2. Dissolve memantine HC1 and hydroxypropyl methyl cellulose OR poly vinyl pyrrolidone in purified water.
3. Add talc to the above solution of step 2.
4. Coat the above solution of step 3 on above seal coated pellets of steps 1.
5. Seal coat the drug coated pellets of step 5 with the solution of hydroxypropyl methylcellulose OR polyvinyl pyrrolidone in purified water.
6. Dissolve ethyl cellulose aqueous dispersion OR ethyl cellulose OR eudragit RL&RS OR kollidone SR to the mixture ofisopropano) and DCM.
7. Coat the drug loaded seal coated pellets of step 5 with solution of step 6.
8. Seal coat the sustained release pellets of step 7 with hydroxylpropyl methyl cellulose OR poly vinyl pyrrolidone solution in purified water.
9. Seal coated sustained release pellets filled into capsule OR Sustained release pellets of step 8 and immediate release pellets of step 4 filled into capsule.
Example: 3 IR composition of Memantine HCl

Ingredients Mg/capsule
A. Base material
Sugar Sphere (600-710 microns) 90.00
B. Drug Layering
Memantine HCI 28.00
Hydroxy propyl methyl cellulose 28.00
Talcum 2.80
Purified water Q.S.

C. Seal Coating (optional)
Hydroxy propyl methyl cellulose 5.60
Purified water Q.S.
Total Weights 154.40
Brief manufacturing Process
1. Dissolve memantine HC1 and hydroxypropyl methyl cellulose in purified water.
2. Add talc to the above solution of step 1.
3. Coat the sugar sphere with above solution of step 2.
4. Optionally seal coat the drug coated sugar sphere of step 3 with the solution of hydroxypropyl melhylcellulose in purified water.
5. Dried the drug pellets.
Example: 4 sustained release coating composition

Ingredients Weight (%wAv)
Ethyl cellulose 75.56
Polyvinyl pyrolidone 13.33
Polyethylene Glycol 11.11
Isopropyl alcohol Q.S.
Dichloromelhane Q.S
Total weights 100.00
Brief manufacturing Process:
1. Dissolve polyethylene glycol in isopropyl alcohol.
2. Added ethyl cellulose and povidone to above solution of step I.
3. Added methylene chloride to above solution of step 2 with continuous stirring till clear solution obtained.

Example: 5
Coat the sustained release coating composition of example 4 on 1R pellets obtained in example 3 and filled into capsules or compressed into tablets.
Example: 6
Blend the 10% IR pellets of memantine of example 3 with 90% ER pellets of example 5 with talc and filled into capsules or compressed into tablets.
In vitro dissolution study:
\n vitro dissolution study of example 5 and 6 was studied In OGD recommended dissolution method and comparative dissolution profile is tabulated below:
Dissolution medium: SGF pH 1.2 without enzyme. Volume: 900 ml. Apparatus: Type 1 (Basket Type), RPM: J00RPM
Tablet: In-vitro dissolution profile

S.No. Time (Hour) % Drug release

Reference Product Examples Example 6
1 0 0 0 0
2 1 12 0 11
3 2 26 13 23
4 40 31 39
5 4 53 46 51
6 5 65 57 60
7 6 75 68 68
8 8 88 82 80
9 12 99 97 93
10 16 102 102 97
Conclusion: Above comparative dissolution profile suggest that dissolution profile of example 5 and 6 are comparable to reference product.

According to present invention, modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts thereof are provided which are particularly suitable for once-a-day oral administration, possessing improved formulation characteristics and release a therapeutically effective amount of the active ingredient over an extended time period.

We claim:
1. A modified release pharmaceutical composition of memanline or its
pharmaceutically acceptable salts comprising:
(a) an optionally seal coated core.
(b) one or more drug layer applied to core comprising memantine or pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient(s),
(c) sustained release coating on drug layer comprising at least one rate controlling polymer(s) and one or more pharmaceutically acceptable excipient(s).

2. The modified release pharmaceutical composition of claim 1 wherein the rate controlling polymer(s) comprises water soluble and /or water insoluble polymer(s).
3. The modified release pharmaceutical composition of claim I wherein the water soluble polymer is selected from hydroxylpropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, sodium lauryl sulphate, polyethylene glycol, sugars, lactose, sucrose, fructose, mannitol, carrageenans, galactomannans, tragacanth. agar-agar, gum arabic, guar gum. xanthan gum, starches, pectins or mixtures thereof.
4. The modified release pharmaceutical composition of claim 1 wherein water insoluble polymer is selected from ethyl cellulose, cellulose acetates, polymethacrylates containing quaternary ammonium group, hydrogenaled vegetable oil. getucire. polyvinyl acetate, cellulose acetate butyrate or mixtures thereof.

5. The modified release pharmaceutical composition according to claim 1 wherein the composition comprises about 40-80% of the core by weight of the total composition.
6. The modified release pharmaceutical composition according to claim 1 wherein the composition comprises about 8-20% of memantine or its pharmaceutically acceptable salts by weight of total composition.
7. The modified release pharmaceutical composition according to claim I wherein the composition comprises about 4~20%o of rate controlling polymer by weight of the total composition.
8. The modified release pharmaceutical composition according to claim I wherein the composition comprises optionally about 2-10%) of immediate release pellets by weight of the total composition.
9. A process for the preparation of modified release pharmaceutical composition of memantine or its pharmaceutically acceptable salts comprising:

(a) an optionally seal coated core.
(b) one or more drug layer applied to inert core comprising memantine or pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient(s),
(c) sustained release coating on drug layer comprising at least one rale controlling polymer(s) and one or more pharmaceutically acceptable excipient(s),

(d) optionally immediate release pellets filled in hard gelatin capsules or compressed in tablets.