CLIAMS:NA ,TagSPECI:TECHNICAL FIELD OF THE INVENTION

The present invention relates to sustained release oral stable pharmaceutical composition (s) comprising active Lacosamide, optionally with one or more pharmaceutically acceptable excipient(s), wherein the said composition is devoid of any rate controlling polymer. The present invention also provides process for the preparation of such compositions which are used for Seizures specifically partial onset seizures in humans or a disease or condition associated with these.

BACKGROUND OF THE INVENTION
Lacosamide is an anticonvulsant with a dual mode of action: selective enhancement of sodium channel inactivation and modulation of CRMP-2 (collapsin response mediator protein-2). This is the R-enantiomer of 2-acetamido-N-benzyl-3-methoxypropionamide, is a chemical compound with anticonvulsant and antinociceptive properties. The drug compound having the adopted name (2)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide and has the structural formula as below:

This medication is developed by UCB, having the approved indication for adjunctive treatment of partial – onset seizures and diabetic neuropathic pain and marketed under the trade name Vimpat® in U.S. market. UCB in November 2007 filed a new drug application with the FDA for use of Lacosamide as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy. The application includes three formulations: tablets, syrup, and an intravenous injection. Lacosamide was also approved in Europe on September 3, 2008 as adjunctive therapy in the treatment of partial-onset seizures, with or without secondary generalization, for patients with epilepsy 16 years or older.
Lacosamide tablets are approved as Initial dose 50 mg twice daily (100 mg per day) and can be increased at weekly intervals by 100 mg/day given as two divided doses up to the recommended maintenance dose of 200 to 400 mg/day, based on individual patient response and tolerability.
Marketed Lacosamide Vimpat® formulations are immediate release formulations and attend the blood plasma concentration immediately after each administration. Further international publication WO2012084126 assigned to innovator UCB specifically discloses Vimpat® tablets releases 98 % of the active agent within 15 minutes after contact with an aqueous medium Due to this immediate release it may leads to drug associated adverse effects. US patent number 5,654,301 discloses amino acid derivatives and RE 38,551 claims Lacosamide specifically.
Some very common side effects associated with Lacosamide is dizziness which may lead to an accidental injury or a fall, double vision, headaches and nausea, where as sustained release formulations of Lacosamide provides a sustained release of the drug that avoids localized precipitation of the drug in a specific area, in turns reduce above mentioned side effects and ultimately increase patient compliance.
International publication WO 2012084126 discloses a solid controlled release Lacosamide formulation for oral administration and an agent for retarding the release of the Lacosamide with having a specific release profile of the active i.e. from about 8.5 wt-% to about 50 wt-% within 1 h, and/or of about 15 wt-% to about 72 wt-% in 2 h, and/or of about 28 wt-% to about 95 wt-% within 4 h, when measured according to USP (edition 24) method, dissolution apparatus 2, in 900 mL of 0.1 N HCI at 75 rpm.
International publication WO2011101863 discloses an extended release stable pharmaceutical composition of Lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients.
International publication WO20110553851 A modified release formulation comprising Lacosamide and modified release polymer. It further discloses the in vitro and in vivo characteristics of the same.

Use of polymer specifically non biodegradable polymers in different kind of controlled release or sustained release dosage forms may involve associated toxicity problems. Further, biodegradable polymers do produce ‘degradation by-products’ that may be tolerated with little adverse reactions within the biological environment. However, it is always advisable to prepare the composition without using any polymer, with having the same desired pharmacodynamic profile as that of the composition with polymer.
All the above listed prior art documents herein above disclose about pharmaceutical composition which involves use of modified release or rate controlling polymer (s) to retard the release of active Lacosamide. The inventors of the present invention with considerable expense of intellectual effort have done extensive research and conducted several experiments to develop a stable pharmaceutical sustained release composition of Lacosamide, which uses simplified conventional manufacturing process and is devoid of any rate controlling polymer to control the release of the drug. Further, being a sustained release composition it has enhanced patient compliance and also provides a safe and effective composition for the management of Seizures specifically partial onset seizures which is particularly devoid of the associated adverse effects of immediate release composition (s).

SUMMARY OF THE INVENTION

It is an objective of the present invention to provide a sustained release stable pharmaceutical composition (s) comprising active Lacosamide optionally with one or more pharmaceutically acceptable excipient(s), wherein the said composition is devoid of any rate controlling polymer (s).

It is an objective of the present invention to provide a sustained release stable pharmaceutical composition which specifically comprising a pharmaceutical clay to control the release of Lacosamide.

It is an objective of the present invention to provide a sustained release stable pharmaceutical composition, wherein the clay is present in intragranular and or extra granular portion of the composition.

It is an objective of the present invention, the clay is selected from the group but not limited to laponite, bentonite, montmorillonite, beidelite, hectorite, saponite and stevensite and the like.

It is an objective of the present invention the clay is present in amount of about 0 to about 23 mg of the total weight of the composition.

It is another objective of the present invention to provide stable pharmaceutical compositions can be formulated as but not limited to tablets, pellets and mini tablets to be filled in capsule.
It is further an objective of the present invention to provide a stable pharmaceutical composition (s) which is present in solid oral dosage form such as tablet, pellets and or mini tablets filled in capsule dosage form which is given as sustained release form.
It is yet another objective of the present invention to provide a process for the sustained release composition of Lacosamide or salts thereof comprising
1. Dissolving Lacosamide in aqueous and or non aqueous solvent mixture or hydro alcoholic mixture
2. Granulating diluent with step 1 solution using a fluid bed granulator followed by drying
3. Mixing the clay with step 2 granules
4. Preparing binder solution and granulating with the material of step 3 followed by drying, sifting and lubrication.
5. Compressing the step 4 material followed by coating

It is another objective of the invention further comprising

1. Sifting Lacosamide, diluent and clay
2. Preparing binder solution and adding it to the material of step 1
3. Lubricating the material of step 2 followed by compression and coating
The compositions of the present invention provide effective prophylactic or therapeutic concentrations of active agent(s) for sustained release of the composition.

It is further objective of the invention, the sustained release Lacosamide releases more than about 20% to about 35% within 1hour, from about 50% to about 70% of Lacosamide within 4 hour and not less than about 80% within 12 hour when tested using USP type II dissolution apparatus at 50 rpm and 37° C temperature in 900ml of 0.1N HCL.

It is further objective of the invention, the sustained release Lacosamide releases more than about 20% to about 35% within 1hour, from about 50% to about 70% of Lacosamide within 4 hour and not less than about 80% within 12 hour when tested using USP type I dissolution apparatus at 100 rpm and 37° C temperature in 900ml of 0.1N HCL.

The present invention provides stable pharmaceutical formulations comprising Lacosamide which are used for the management of diseases or disorders associated with Seizures specifically partial onset seizures in humans, comprising administering a formulation containing an effective amount of the active agent.

BRIEF DESCRIPTION OF THE DRAWINGS:
Fig 1 shows a comparative dissolution profile of sustained release dosage form of Lacosamide of Example 1 (composition without polymer, Micro labs) product Vs Example 3 and 4 (composition with polymer), in 0.1 N HCL, 37 ° C ± 0.5 ° C, 50 rpm, USP Paddle.

DETAILED DESCRIPTION OF THE INVENTION:

It is believed that one skilled in the art can based upon the description herein; utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.

The present invention provides a sustained release stable pharmaceutical composition (s) comprising Lacosamide optionally with one or more pharmaceutically acceptable excipient(s), wherein the said composition is devoid of any rate controlling polymer (s).

The inventor of the instant invention have found that when Lacosamide are formulated in to sustained release compositions without using any rate controlling polymer(s), it maintains a acceptable sustained release drug profile throughout the defined time periods when tested in vitro and are equally stable when compared to the other reference compositions using rate controlling polymer(s).

The term “Lacosamide” whenever it appears includes Lacosamide in the form of the free base.

The disclosed invention provides a sustained release composition of Lacosamide, where in release is being governed by the use of a “release controlling carrier”.

The “release controlling carrier” in the context of the invention refers to a carrier used in the sustained release composition (s) to control or sustained the release of Lacosamide and must not be interpreted physicochemically as a polymer.

The “suitable release controlling carrier” includes one or more stable pharmaceutical clay selected from the group but not limited to laponite, bentonite, montmorillonite, beidelite, hectorite, saponite and stevensite and the like. Specifically instant invention uses bentonite for release controlling of the Lacosamide.
Clay are widely used in numerous industrial applications as fillers in production of paper, plastics, as pigments in cosmetics; corrosion proof agents in coatings; anti-caking agents in chemical industry; UV-, heat-stable and under-water agents in paintings, etc.
In an embodiment bentonite is used in an amount from about 0 to about 23 mg of total weight of the composition.

The term 'stable' as used herein refers to chemical stability of Lacosamide in solid dosage forms wherein there is no significant change in impurities percentages and dissolution profile when kept at accelerated temperature and humidity conditions.

Sustained release composition include, inter alia, those compositions described elsewhere herein above and throughout the description as “extended release”, “delayed release”, “prolonged released”, “time release” and/or “rate controlled” compositions or dosage forms.
The term “sustained release compositions” herein refers to any compositions or dosage form which comprises an active drug and which is formulated to provide a or being understood to be a composition or dosage form which does not release a substantial portion of the active content for dissolution and absorption until it passes through the stomach and reaches the small intestine.

The term “sustained release stable pharmaceutical composition” includes a stable pharmaceutical composition that encompasses one or more individual coated or un coated units, which present in the form of but not limited to tablets, pellets and mini tablets filled in capsules.

The sustained release stable pharmaceutical composition of Lacosamide in accordance with the present invention exhibits a dissolution profile which is suitable for once a day dosage regimen.

In a preferred embodiment of the present invention, the sustained release Lacosamide releases more than about 20% to about 35% within 1hour, from about 50% to about 70% of Lacosamide within 4 hour and not less than about 80% within 12 hour when tested according to USP type II dissolution apparatus at 50 rpm and 37° C temperature in 900ml of 0.1N HCL.

In a preferred embodiment of the present invention, the sustained release Lacosamide releases more than about 20% to about 35% within 1hour, from about 50% to about 70% of Lacosamide within 4 hour and not less than about 80% within 12 hour when tested according to USP type I dissolution apparatus at 50 rpm and 37° C temperature in 900ml of 0.1N HCL
The present invention also provides processes for preparation of the formulations/compositions of Lacosamide. In one embodiment, the process comprises the steps of:
1. Dissolving Lacosamide in aqueous and or non aqueous solvent mixture or hydro alcoholic mixture
2. Granulating diluent with step 1 solution using fluid bed granulator followed by drying
3. Mixing the clay with step 2 granules
4. Preparing binder solution and granulating with the material of step 3 followed by, sifting and lubrication.
5. Compressing the step 4 material followed by coating

In another embodiment the process comprising

1. Sifting Lacosamide, diluent and clay
2. Preparing binder solution and adding it to the material of step 1
3. Lubricating the material of step 2 followed by compression and coating

The compositions of the present invention provide effective prophylactic or therapeutic concentrations of active agent(s) for sustained release of the composition.
The inventors of the present invention with considerable expense of intellectual effort have done extensive research and conducted several experiments to develop a stable pharmaceutical sustained release composition of Lacosamide, which uses simplified conventional manufacturing process and is devoid of any rate controlling polymer to control the release of the drug. Further, being a sustained release composition it has enhanced patient compliance and also provides a safe and effective composition for the management of Seizures specifically partial onset seizures disease which is particularly devoid of the associated adverse effects of immediate release compositions.
It would be note worthy that prior art patent document uses polymer to control the release of Lacosamide, where as inventor of the instant invention developed an alternative composition which uses clay as a release controlling carrier instead of any polymers and achieve comparative release profiles. Further, it is administered as a once a day dosage form, in turn has enhanced patient compliance when compared to it counter part marketed Lacosamide immediate release Vimpat® composition.
In another embodiment of the present invention, the pharmaceutically acceptable excipient(s) of the present invention are selected from but not limited to a group comprising diluents, lubricants, binders, surfactants, colorants, glidants, complexing agents and the like known to the art used either alone or in combination thereof.
Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, starch, colloidal silicon dioxide such as, dibasic calcium phosphate, saccharides, and/or mixtures of the foregoing. Examples of diluents include microcrystalline celluloses such as Avicel® PH101, Avicel® PH102, Aerosil® 200, Avicel® PH112, Avicel® PH200, Avicel® PH301 and Avicel® PH302; lactose such as lactose monohydrate, lactose anhydrous and Pharmatose® DCL21, including anhydrous, monohydrate and spray dried forms; dibasic calcium phosphate such as Emcompress®; starch; sucrose; glucose, and the like used either alone or in combination thereof.
Suitable lubricants are selected from but not limited to a group comprising talc; stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil and the like used either alone or in combination thereof.

Suitable binder useful in the present invention is selected from but not limited to a group comprising polyvinylpyrrolidone (e.g. PVP K-90 or PVP K-30), copovidone (e.g. Plasdone® S630), cellulosic polymers (e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or the like), gums such as xanthan, alginates such as sodium alginate, polyvinylacetate, and the like used either alone or in combination thereof. More preferably, copovidone (e.g. Plasdone® S630) is useful as a binder.

The clay is selected from the but not limited to laponite, bentonite, montmorillonite, beidelite, hectorite, saponite and stevensite and the like.

Suitable plasticizers are used in an over-coating layer to improve the mechanical properties of a film formed by a polymeric substance.
These agents are selected from but not limited to a the group comprising wax, linoline-type alcohols, a gelatine, a polyethylene glycol, a polypropylene glycol, triacetin, tributyl citrate, tri ethyl citrate, dibutyl sebacate, medium chain length triglyceride fatty acids, resin acid, long chain fatty acids (e.g. stearic acid, palmitic acid) and the like used either alone or in
combination thereof.

Suitable Glidant are selected from but not limited to a group comprising silica; colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil® 200, magnesium trisilicat, powdered cellulose, starch, talc and the like used either alone or in combination thereof. Preferably colloidal silica anhydrous or/and colloidal silicon dioxide are used.

The present invention provides using stable pharmaceutical formulations of Lacosamide for the management of a disease or condition associated with Seizures in humans, comprising administering a formulation containing an effective amount of Lacosamide.

Table 1

Medium Batch Example 1
Micro Labs (without polymer) Example-3
(with polymer) Example-4
(with polymer)
Time in hrs % Release % Release % Release

0.1 N HCL

0.0 0.0 0.0 0.0
1.0 23.8 12.0 9.6
4.0 51.7 30.5 27.8
12.0 93.0 63.6 77.2

Above Table 1 represents initial comparative % drug release of both the Example 1 (composition without polymer, Micro Labs) and Example 3 and Example 4 (composition with polymer) when subjected to specified dissolution conditions. It would be note worthy that the % drug release of Example 1 has a comparable similar profile with Example 3 (with rate controlling polymer). This percentage release of the examples shows both the products has comparative sustained action throughout the time period when tested in vitro. A graphical comparative representation has been produced in fig. 01 for better clarity.
The term ‘q.s.’ wherever appears in the examples is an abbreviation for ‘quantity sufficient’ which is the amount of the vehicle in such quantities that is just sufficient for its use in the composition of the present invention.

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

Example –1
Table-2: Pharmaceutical composition comprising bentonite
SN. Ingredients Quantity/tab (mg)
Granulation I
1. Lacosamide 200.00
2. Colloidal silicon dioxide (Aerosil 200) 100.00
3. Isopropyl alcohol & water mixture q.s.
Granulation II
4. Bentonite 23.00
5. Polyvinyl pyrollidone (PVPK 30) 20.00
6. Purified Water q.s
Lubrication
7. Magnesium Stearate 3.00
Coating
9. Opadry 10.38
10. Purified Water q.s

Procedure:
i) Drug Lacosamide was mixed with a mixture of isopropyl alcohol and water.
ii) Aerosil 200 was granulated by using step i solution in a rapid mixture granulator or a fluid bed processor.
iii) Step ii granules were dried by using a fluid bed dryer/ processor followed by sifting through # 30 mesh.
iv) Bentonite was shifted through suitable mesh
v) Step iii and step iv materials were mixed together in a rapid mixture granulator.
vi) Polyvinyl pyrollidone was dissolved in water.
vii) Step v material were granulated by using solution of step vi.
viii) Materials of step vii were dried and passed through suitable mesh.
ix) Materials of step viii were lubricated by using magnesium stearate.
x) Material of step ix were compressed to obtained the desired dosage form
xi) Dosage form of step x were coated with Opadry

Example –2
Table 3 Pharmaceutical composition comprising bentonite

SN. Ingredients Quantity/tab (mg)
Dry Mix
1. Lacosamide 200.00
2. Colloidal silicon dioxide (Aerosil 200) 100.00
3. Bentonite 23.00
Binder Solution
5. Polyvinyl pyrollidone (PVPK 30) 20.00
6. Purified Water /IPA q.s
Lubrication
7. Magnesium Stearate 3.00
Coating
9. Opadry 10.38
10. Purified Water q.s

Procedure:
i) Lacosamide, colloidal silicon dioxide (Aerosil 200) and Bentonite were weighted and shifted through suitable mesh and mixed together.
ii) Binder solution was prepared by mixing Polyvinyl pyrollidone with purified water
iii) Material of step i was mixed with solution of step ii in a rapid mixture granulator
iv) Bentonite was shifted through suitable mesh
v) Material of step iv were lubricated by using magnesium stearate
vi) Material of step v were compressed to obtained the desired dosage form
vii) Dosage form of step vi were coated with Opadry

Example –3
Table 4 Pharmaceutical composition (comparative) comprising polymer

SN. Ingredients Quantity/tab (mg)
Dry Mix
1. Lacosamide 19.05
2. Hypromellose 28.57
3. Microcrystalline cellulose 23.81
5. Copovidone 23.81
6. Aerosil 2.86
Lubrication
7. Magnesium Stearate 1.90
8. IPA q.s.

Procedure:
i) Lacosamide, Hypromellose and Microcrystalline cellulose were shifted through 30 # sieve and mixed together
ii) Binder solution was prepared by dissolving copovidone was in solvent.
iii) Material of step i were mixed with solution of step ii
iv) Material of step iii were dried and shifted through 20# sieve
v) Microcrystalline cellulose and Aerosil were shifted through 40# sieve and mixed with the material of step iv
vi) Material of step v were lubricated by using magnesium stearate
vii) Material of step vi were compressed followed by coating with Opadry.

Example –4
Table 5 Pharmaceutical composition comprising polymer

SN. Ingredients Quantity/tab (mg)
Dry Mix
1. Lacosamide 32.26
2. Microcrystalline cellulose 28.23
3. Polyvinylpyrrolidone 4.03
4. Polyethylene Oxide 24.19
5. Hypromellose 8.06
6. Solvent q.s.
7. Colloidal silicon dioxide 1.61
8. Magnesium Stearate 1.61

Procedure:
i) Al the ingredients were shifted through sieve
ii) Lacosamide and microcrystalline cellulose were shifted through 30 # sieve and mixed together
iii) Binder solution was prepared by using polyvinyl pyrollidone in a solvent
iv) Material of step ii were mixed with solution of step iii followed by drying
v) Material of step iv were shifted through suitable mesh
vi) Material of step v were mixed with polyethylene oxide, hypromellose to form a uniform blend
vii) Material of step vi were mixed with colloidal silicon dioxide and lubricated with magnesium stearate for 5 minute
viii) Material of step vii were compressed in to obtained the desired dosage form followed by coating with either aqueous or semi aqueous solution.

Dated this ___ day of May, 2013

Fig 1: comparative dissolution profile of sustained release dosage form of Lacosamide of Example 1 (Composition without polymer, Micro lab) Vs Example 3 and 4 (composition with polymer).

ABSTRACT

The present invention relates to sustained release oral stable pharmaceutical compositions comprising active Lacosamide, optionally with one or more pharmaceutically acceptable excipient(s), wherein the said composition is devoid of any rate controlling polymer. The present invention also provides process for the preparation of such compositions.