WO2011101863A2 - Extended release pharmaceutical compositions of lacosamide - Google Patents

Extended release pharmaceutical compositions of lacosamide Download PDF

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Publication number
WO2011101863A2
WO2011101863A2 PCT/IN2011/000085 IN2011000085W WO2011101863A2 WO 2011101863 A2 WO2011101863 A2 WO 2011101863A2 IN 2011000085 W IN2011000085 W IN 2011000085W WO 2011101863 A2 WO2011101863 A2 WO 2011101863A2
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WO
WIPO (PCT)
Prior art keywords
lacosamide
extended release
pharmaceutical composition
release pharmaceutical
salts
Prior art date
Application number
PCT/IN2011/000085
Other languages
French (fr)
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WO2011101863A3 (en
Inventor
Sunilendu Bhushan Roy
Sushrut Krishnaji Kulkarni
Maulik Kiritkumar Panchal
Bhushan Vijay Joshi
Raju Dantuluri Prudhvi
Original Assignee
Cadila Healthcare Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2011101863A2 publication Critical patent/WO2011101863A2/en
Publication of WO2011101863A3 publication Critical patent/WO2011101863A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • the present invention relates to extended release pharmaceutical compositions of lacosamide or salts thereof with once a daily dosage regimen.
  • the compositions of the invention provide extended therapeutically effective plasma levels over a twenty four hour period with reduced incidences of neuropsychiatric side effects.
  • the invention also relates to process of making such compositions.
  • Lacosamide is an anticonvulsant drug useful in the treatment of central nervous system disorders such as epilepsy. This drug is also useful in the treatment of pain, particularly neuropathic pain such as diabetic neuropathic pain. Chemically, lacosamide is (R)-2-acetamido-N-benzyl-3-methoxypropionamide.
  • Lacosamide acts by enhancing slow inactivation of voltage gated sodium channels.
  • Voltage gated sodium channels are the membrane proteins responsible for generating the neuronal action potential, the all or none electrical event which causes neurons to release neurotransmitter.
  • voltage gated sodium channels undergo fast inactivation, a process which takes a few milliseconds. This inactivation prevents the channel from opening, and helps end the action potential.
  • Lacosamide only affects neurons which are depolarized or active for long periods of time, typical of neurons at the focus of an epileptic focus.
  • lacosamide is administered as conventional immediate release tablets.
  • the current dosage regimen includes minimum twice daily administration and it can beyond that also based on patient response. It is marketed in USA under the brand name Vimpat ® by UCB in the strengths of 50, 100, 150 and 200 mg.
  • U.S. Patent Nos. 5,654,301 and 5,773,475 discloses lacosamide useful for treating CNS disorders and pharmaceutical compositions thereof.
  • U.S. Patent Application No. 2009/0298947 discloses different polymorphic and amorphous forms of lacosamide, and pharmaceutical compositions containing the same.
  • U.S. Patent No. 6,884,910 discloses method of alleviating pain in patient suffering therefrom comprising administering to said patient an analgesic effective amount of lacosamide and related amino acid derivatives.
  • U.S. Patent No. 7,718, 161 discloses use of lacosamide or pharmaceutically acceptable salts thereof for treating motoneron disorders.
  • Immediate release regimen is not optimal because patient compliance decreases as the frequency of taking a drug increases. Moreover, after oral administration, lacosamide is completely absorbed (absolute bioavailability of approximately 100%). Food does not affect the rate and extent of absorption. For convulsion therapy, it is very important to control the seizure without additional discomfort. Thus, administration of an immediate-release tablet can lead to greater frequency of adverse pharmacological events due to the fast rate of absorption.
  • an extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients.
  • a matrix-type extended release pharmaceutical composition comprising lacosamide or salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers.
  • an extended release pharmaceutical composition comprising multiple-unit particles comprising lacosamide or salts thereof and one or more pharmaceutically acceptable rate-controlling polymers.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.
  • an extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients, wherein said composition exhibits a dissolution profile of lacosamide or salts thereof such that at least 80% of lacosamide or salt thereof is released from about 8 hour to about 24 hour after administration.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.
  • an extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients, wherein said composition retains at least 80% of the potency of lacosamide
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.
  • a method for treating partial onset seizures in patients with epilepsy and/or preventing visual disturbance or PR prolongation comprises administering an extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.
  • the inventors of the present invention have surprisingly found that it is possible to diminish incidences of neuropsychiatric side effects like visual disturbances and PR interval prolongation by extending drug release rate.
  • lacosamide or salts thereof when formulated into extended release compositions using one or more rate-controlling polymers, it may prevent peak-trough fluctuations in plasma levels and thus maintains therapeutically effective plasma levels of lacosamide over an extended period of time. Furthermore, the extended release formulation may allow for a reduced frequency of dosing, e.g., once a day dosing, and thus can improve patient compliance.
  • the extended release pharmaceutical composition of lacosamide or salts thereof comprises one or more pharmaceutically acceptable rate- controlling polymers and one or more pharmaceutically acceptable excipients, wherein the composition exhibits no significant difference in both rate and extent of absorption of lacosamide or salt thereof as compared to immediate release formulation of lacosamide marketed under trade name Vimpat® administered twice daily.
  • the extended release pharmaceutical composition of lacosamide or salts thereof in accordance with the present invention exhibits a dissolution profile which is suitable for once a day dosage regimen.
  • the extended release composition of the present invention exhibits a dissolution profile of lacosamide or salts thereof in water or simulated gastric fluid such that at least 10% of lacosamide is released after 2 hours, at least 20% of lacosamide is released after 4 hours, at least 40% of lacosamide is released after 8 hours, at least 60% lacosamide is released after 10 hours, and at least 80% lacosamide is released within 24 hours.
  • the extended release pharmaceutical composition of the present invention exhibits a dissolution profile of lacosamide or salts thereof in water or simulated gastric fluid such that at least 5% of lacosamide is released after 1 hour, at least 26% of lacosamide is released after 4 hours and at least 75% of lacosamide is released after 10 hours.
  • the extended release pharmaceutical composition of the present invention exhibits a dissolution profile of lacosamide or salts thereof in water or simulated gastric fluid such that at least 10% of lacosamide is released after 1 hour, at least 25% of lacosamide is released after 4 hours, at least 60% of lacosamide is released after 6 hour and at least 90% of lacosamide is released within 24 hours.
  • sustained release means release of the active agent at such a rate that blood (e. g., plasma) levels are maintained within a therapeutic range but below toxic levels for at least about 4 hours, preferably at least about 6 hours after administration at steady-state.
  • steady-state means that a plasma level for a given active agent has been achieved and which is maintained with subsequent doses of the drug at a level which is at or above the minimum effective therapeutic level and is below the minimum toxic plasma level for a given active agent.
  • lactyamide used throughout the specification refers to not only lacosamide per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
  • the amount of lacosamide or salt thereof in the extended release composition of the present invention ranges from about 30% w/w to about 60% w/w.
  • Suitable “rate-controlling polymers” may include one or more of hydrophilic polymers and hydrophobic polymers.
  • the preferred amount of rate-controlling polymer in the extended release formulation ranges from about 5% w/w to about 75% w/w of the composition.
  • 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; polyacrylates, methyl acrylates, polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or acrylamide derivatives and the like.
  • the preferred hydrophilic polymer is hydroxypropyl methylcellulose or any commercially available grade thereof such as Methocel.
  • Preferred hydrophilic polymer is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose or mixture thereof.
  • Suitable hydrophobic polymers include one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil and its derivatives, e.g.
  • Preferred hydrophobic polymer is hydrogenated vegetable oil and its derivatives.
  • the polymers used can also be eroding or non-eroding or combination of both.
  • the polymers, which may be used for bioadhesion, are described below.
  • Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such as pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium alginate.
  • proteins e.g., hydrophilic proteins
  • the synthetic polymer is typically selected from but are not limited to polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly( valeric acid), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers or mixtures thereof.
  • the ratio of amount of lacosamide or salts thereof to rate-controlling polymer ranges from 1 : 10 to 10: 1.
  • a stable extended release pharmaceutical composition comprising lacosamide or salts thereof and one or more pharmaceutically acceptable rate-controlling polymers, which composition retains at least 80% of the potency of lacosamide or salts thereof in the said pharmaceutical composition after storage for three months at 40° C and 75% relative humidity.
  • Suitable dosage form comprises one or more of tablets, multilayered tablets, capsules, pellets, granules, spheroids, beads, minitablets in capsule, pellets in capsule, granules in capsule, powder. Further the powder or granules can be suspended to give a pharmaceutically acceptable oral suspension.
  • the extended release composition of lacosamide or its salt is preferably developed into dosage forms such as matrix-tablets/granules/pellets, coated tablets/granules/pellets or multiple unit particles which can be filled into capsules or compressed to . form tablets.
  • the extended release composition is not particularly limited as long as it is an oral preparation.
  • tablets, granules, fine granules, pellets, mini/micro tablets, capsules and the like can be manufactured in the present invention.
  • Capsules can be packed with one or more tablets, granules or fine granules based on the matrix type extended release preparation according to the present invention.
  • hard capsules can be packed with multiple small-diameter mini-tablets based on the matrix type extended release preparation, or with the aforementioned granules or fine granules based on the matrix type extended release preparation, or with both tablets based on the matrix extended release preparation and granules or fine granules based on the matrix type extended release preparation.
  • the matrix type extended release preparation can also be given a film coating as necessary.
  • the extended release pharmaceutical composition in accordance with the present invention comprises multiple-unit particles comprising lacosamide or salts thereof and one or more pharmaceutically acceptable rate- controlling polymers.
  • the extended release pharmaceutical composition comprises multiple-unit particles comprising lacosamide or salts thereof coated with one or more pharmaceutically acceptable rate-controlling polymers.
  • the extended release pharmaceutical composition comprises multiple-unit particles comprising matrix of lacosamide or salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers, and optionally said multiple-unit particles are further coated with one or more rate- controlling polymers.
  • the extended release pharmaceutical composition comprises multiple-unit particles comprising inert core made up of water soluble material (e.g. lactose) or water insoluble material (e.g. microcrystalline cellulose) coated with consecutive or alternate layers of lacosamide and one or more rate- controlling polymer/s.
  • inert core made up of water soluble material (e.g. lactose) or water insoluble material (e.g. microcrystalline cellulose) coated with consecutive or alternate layers of lacosamide and one or more rate- controlling polymer/s.
  • the extended release composition can also be given a film coating as necessary. It should be noted that the presence or absence of a hydrophilic film coating on the extended release preparation according to the present invention has very little effect on the dissolution profile of memantine or salt thereof.
  • the 'non-functional coating' or 'film coating' may comprise polymers like hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, copolymer of vinyl pyrrolidone and vinyl acetate; plasticizers like polyethylene glycol, triacetin, dibutyl sebecate and diethyl tartrate; opacifying agents like titanium dioxide and talc; and coloring agents. Examples of such nonfunctional coats are commercially available Opadry® compositions.
  • compositions as described herein may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet or dry granulation, slugging, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion-spheronization, spray drying and solvent evaporation.
  • the process of manufacturing an extended release pharmaceutical composition of lacosamide or salts thereof in accordance with the present invention comprises- providing a matrix and/or coated core comprising lacosamide or salts thereof, one or more rate-controlling polymer/s and one or more pharmaceutically acceptable excipients.
  • the extended release compositions may be prepared by mixing and granulating lacosamide or salts thereof with one or more rate-controlling polymers along with one or more pharmaceutically acceptable excipients to form granules.
  • the granules can be dried.
  • the dried granules can be milled, mixed with other pharmaceutically acceptable excipients, lubricated and formulated into suitable dosage form. Further, the dosage form can be coated with one or more rate-controlling polymers.
  • the process of preparing extended release pharmaceutical composition comprising multiple-unit particles, which process comprises steps of-
  • inert core made up of water soluble (e.g. lactose or sugar) or water insoluble material (e.g. microcrystalline cellulose) with lacosamide or salts thereof with one or more rate-controlling polymer to form drug coated pellets,
  • water soluble e.g. lactose or sugar
  • water insoluble material e.g. microcrystalline cellulose
  • the extended release pharmaceutical composition comprising lacosamide or salts thereof further may comprise additional anticonvulsant agent, which can be selected from one or more active agent/s selected from therapeutic category of antipsychotic agents, anticonvulsants and antidepressant agents, typical antipsychotics and atypical antipsychotics.
  • the pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.
  • Suitable fillers may include one or more of microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols_such as mannitol, sorbitol, erythritol and the like.
  • Suitable disintegrants may include one or more of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross- linked polyvinylpyrrolidone and the like.
  • Suitable binders may include one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like.
  • plasticizers include, but not limited to glycerin fatty acid esters; triethyl citrate; propylene glycol; polyethylene glycol and the like.
  • Suitable lubricants and glidants may include one or more of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid,.hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; and the like
  • the invention provides a method for treating partial onset seizures in patients with epilepsy and/or preventing visual disturbance or PR prolongation, wherein method comprises administering an extended release pharmaceutical composition of lacosamide or salts thereof.
  • Lacosamide, hydroxypropyl cellulose, lactose monohydrate were mixed and granulated with isopropyl alcohol. Granules were dried and mixed with lactose anhydrous, talc, magnesium stearate, and colloidal silicon dioxide and the compressed into tablets using suitable tooling.
  • Table 2 provides dissolution data for lacosamide tablet prepared as per Example 1.
  • USP Type I apparatus lOOrpm
  • 900mf of water and 0.1N HC1 was used as medium.
  • Table 4 provides dissolution data for lacosamide tablet prepared as per Example 2.
  • USP Type I apparatus lOOrpm
  • 900ml of water was used as medium.
  • Lacosamide, hydroxypropyl cellulose (HXF), lactose monohydrate were mixed and granulated with isopropyl alcohol. Granules were dried and mixed with lactose anhydrous, talc, magnesium stearate, and colloidal silicon dioxide and then compressed into tablets using suitable tooling.
  • Table 6 provides dissolution data for lacosamide tablet prepared as per Example 3.
  • USP Type I apparatus lOOrpm
  • 900ml of water was used as medium.
  • Lacosamide, hydrogenated castor oil, and hydroxypropyl cellulose were mixed and granulated with isopropyl alcohol and water. Granules were dried and mixed with lactose anhydrous, talc, and magnesium stearate and then compressed into tablets using suitable tooling.
  • Table 8 provides dissolution data for lacosamide tablet prepared as per Example 4.
  • USP Type I apparatus lOOrpm
  • IN HCI 0.
  • Lacosamide, hydrogenated castor oil, and hydroxypropyl cellulose were mixed and granulated with isopropyl alcohol and water. Granules were dried and mixed with lactose anhydrous, talc, and magnesium stearate and then compressed into tablets using suitable tooling.
  • Table 10 provides dissolution data for lacosamide tablet prepared as per Example 5.
  • USP Type I apparatus lOOrpm
  • IN HCI 0.
  • Lacosamide and lactose monohydrate were mixed and granulated using binder solution of hydroxypropyl methylcellulose in isopropyl alcohol and water. Granules were dried and lubricated with talc, magnesium stearate, and colloidal silicon dioxide and the compressed into tablets using suitable tooling.
  • Dispersion of ammoniomethacrylate copolymers type A, type B, triethyl citrate, talc and coloring agent was sprayed onto core tablets in a suitable coating pan to yield coated tablets.
  • Table 12 Dissolution data
  • Table 12 provides dissolution data for lacosamide tablet prepared as per Example 6.
  • USP Type I apparatus lOOrpm
  • 900mf of water was used as medium.
  • Table 14 provides dissolution data for lacosamide tablet prepared as per Example 6.
  • USP Type I apparatus lOOrpm
  • 900mf of water was used as medium.

Abstract

An extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients.

Description

EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS OF LACOSAMIDE
Field of the Invention
The present invention relates to extended release pharmaceutical compositions of lacosamide or salts thereof with once a daily dosage regimen. The compositions of the invention provide extended therapeutically effective plasma levels over a twenty four hour period with reduced incidences of neuropsychiatric side effects. The invention also relates to process of making such compositions.
Background of the Invention
Lacosamide is an anticonvulsant drug useful in the treatment of central nervous system disorders such as epilepsy. This drug is also useful in the treatment of pain, particularly neuropathic pain such as diabetic neuropathic pain. Chemically, lacosamide is (R)-2-acetamido-N-benzyl-3-methoxypropionamide.
Lacosamide acts by enhancing slow inactivation of voltage gated sodium channels. Voltage gated sodium channels are the membrane proteins responsible for generating the neuronal action potential, the all or none electrical event which causes neurons to release neurotransmitter. During an action potential voltage gated sodium channels undergo fast inactivation, a process which takes a few milliseconds. This inactivation prevents the channel from opening, and helps end the action potential. Lacosamide only affects neurons which are depolarized or active for long periods of time, typical of neurons at the focus of an epileptic focus.
Presently, lacosamide is administered as conventional immediate release tablets. The current dosage regimen includes minimum twice daily administration and it can beyond that also based on patient response. It is marketed in USA under the brand name Vimpat® by UCB in the strengths of 50, 100, 150 and 200 mg.
U.S. Patent Nos. 5,654,301 and 5,773,475 discloses lacosamide useful for treating CNS disorders and pharmaceutical compositions thereof.
U.S. Patent Application No. 2009/0298947 discloses different polymorphic and amorphous forms of lacosamide, and pharmaceutical compositions containing the same. U.S. Patent No. 6,884,910 discloses method of alleviating pain in patient suffering therefrom comprising administering to said patient an analgesic effective amount of lacosamide and related amino acid derivatives.
U.S. Patent No. 7,718, 161 discloses use of lacosamide or pharmaceutically acceptable salts thereof for treating motoneron disorders.
Immediate release regimen is not optimal because patient compliance decreases as the frequency of taking a drug increases. Moreover, after oral administration, lacosamide is completely absorbed (absolute bioavailability of approximately 100%). Food does not affect the rate and extent of absorption. For convulsion therapy, it is very important to control the seizure without additional discomfort. Thus, administration of an immediate-release tablet can lead to greater frequency of adverse pharmacological events due to the fast rate of absorption.
Conventional immediate release lacosamide formulation shows high Cmax followed by high Css which leads to severe neuropsychiatry side effects like visual disturbance and prolongation of PR interval (the time between the start of atrial systole and the start of ventricular systole, measure as the P-R interval of electrocardiogram) leading to AV (atrioventricular) node blockage. Also, highly fluctuating blood concentrations of lacosamide may produces unwanted side effects as described above. Such side effects may have limited the practical usefulness of oral lacosamide.
For the foregoing reasons, there is a need for improved lacosamide formulations which are capable of stable therapeutic effects by maintaining a constant serum level for an extended period in order to avoid the 'peak and trough' side effects and which can also control mean plasma concentration of lacosamide in the therapeutic window and maintain steady state level of the drug below minimum toxic concentration, thus minimizing the known toxic effects of lacosamide. The compositions of the invention overcome all the encountered problems exemplified above. Moreover, the formulation should be easy and inexpensive to manufacture and convenient for the patient to use. Summary of the Invention
In one general aspect, there is provided an extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients. In another general aspect, there is provided a matrix-type extended release pharmaceutical composition comprising lacosamide or salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers.
In another general aspect, there is provided an extended release pharmaceutical composition comprising multiple-unit particles comprising lacosamide or salts thereof and one or more pharmaceutically acceptable rate-controlling polymers.
Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.
In another general aspect, there is provided an extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients, wherein said composition exhibits a dissolution profile of lacosamide or salts thereof such that at least 80% of lacosamide or salt thereof is released from about 8 hour to about 24 hour after administration.
Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.
In another general aspect, there is provided an extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients, wherein said composition retains at least 80% of the potency of lacosamide
o
or salts thereof after storage for 3 months at 40 C /75% RH.
Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like. In another general aspect, there is provided a process of preparing the extended release pharmaceutical composition of lacosamide or salts thereof comprising-
(a) mixing lacosamide or salt thereof with one or more pharmaceutically acceptable rate-controlling polymer/s optionally with one or more pharmaceutically acceptable excipients
(b) granulating or compression molding of above mixture to form granules, pellets, tablets and minitablets.
In another general aspect, there is provided a method for treating partial onset seizures in patients with epilepsy and/or preventing visual disturbance or PR prolongation, wherein said method comprises administering an extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients.
Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.
. The details of one or more embodiments of then invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.
Detailed Description of the Invention
The inventors of the present invention have surprisingly found that it is possible to diminish incidences of neuropsychiatric side effects like visual disturbances and PR interval prolongation by extending drug release rate.
The inventors have further found that when lacosamide or salts thereof are formulated into extended release compositions using one or more rate-controlling polymers, it may prevent peak-trough fluctuations in plasma levels and thus maintains therapeutically effective plasma levels of lacosamide over an extended period of time. Furthermore, the extended release formulation may allow for a reduced frequency of dosing, e.g., once a day dosing, and thus can improve patient compliance.
In an embodiment, the extended release pharmaceutical composition of lacosamide or salts thereof comprises one or more pharmaceutically acceptable rate- controlling polymers and one or more pharmaceutically acceptable excipients, wherein the composition exhibits no significant difference in both rate and extent of absorption of lacosamide or salt thereof as compared to immediate release formulation of lacosamide marketed under trade name Vimpat® administered twice daily.
The extended release pharmaceutical composition of lacosamide or salts thereof in accordance with the present invention exhibits a dissolution profile which is suitable for once a day dosage regimen.
In a preferred embodiment, the extended release composition of the present invention exhibits a dissolution profile of lacosamide or salts thereof in water or simulated gastric fluid such that at least 10% of lacosamide is released after 2 hours, at least 20% of lacosamide is released after 4 hours, at least 40% of lacosamide is released after 8 hours, at least 60% lacosamide is released after 10 hours, and at least 80% lacosamide is released within 24 hours.
In another preferred embodiment, the extended release pharmaceutical composition of the present invention exhibits a dissolution profile of lacosamide or salts thereof in water or simulated gastric fluid such that at least 5% of lacosamide is released after 1 hour, at least 26% of lacosamide is released after 4 hours and at least 75% of lacosamide is released after 10 hours.
In yet another preferred embodiment, the extended release pharmaceutical composition of the present invention exhibits a dissolution profile of lacosamide or salts thereof in water or simulated gastric fluid such that at least 10% of lacosamide is released after 1 hour, at least 25% of lacosamide is released after 4 hours, at least 60% of lacosamide is released after 6 hour and at least 90% of lacosamide is released within 24 hours.
The term "extended release" as used hereinbefore and throughout the description includes extended release, controlled release, modified release and delayed release. The term sustained release means release of the active agent at such a rate that blood (e. g., plasma) levels are maintained within a therapeutic range but below toxic levels for at least about 4 hours, preferably at least about 6 hours after administration at steady-state. The term "steady-state" means that a plasma level for a given active agent has been achieved and which is maintained with subsequent doses of the drug at a level which is at or above the minimum effective therapeutic level and is below the minimum toxic plasma level for a given active agent. The term "lacosamide" used throughout the specification refers to not only lacosamide per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
It is possible to use any salts and free base form of lacosamide, including polymorphs, hydrates, solvates or amorphous forms.
In an embodiment, the amount of lacosamide or salt thereof in the extended release composition of the present invention ranges from about 30% w/w to about 60% w/w.
Suitable "rate-controlling polymers" may include one or more of hydrophilic polymers and hydrophobic polymers. The preferred amount of rate-controlling polymer in the extended release formulation ranges from about 5% w/w to about 75% w/w of the composition.
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; polyacrylates, methyl acrylates, polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or acrylamide derivatives and the like. The preferred hydrophilic polymer is hydroxypropyl methylcellulose or any commercially available grade thereof such as Methocel. Preferred hydrophilic polymer is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose or mixture thereof.
Suitable hydrophobic polymers include one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil and its derivatives, e.g. hydrogenated castor oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, acrylate and phthalate polymers and copolymers such as poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyI acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene terephthalate) and the like. Preferred hydrophobic polymer is hydrogenated vegetable oil and its derivatives.
The polymers used can also be eroding or non-eroding or combination of both. The polymers, which may be used for bioadhesion, are described below.
Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such as pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium alginate.
When the bioadhesive polymer is a synthetic polymer, the synthetic polymer is typically selected from but are not limited to polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly( valeric acid), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers or mixtures thereof.
In a preferred embodiment, the ratio of amount of lacosamide or salts thereof to rate-controlling polymer ranges from 1 : 10 to 10: 1.
In a further embodiment, a stable extended release pharmaceutical composition comprising lacosamide or salts thereof and one or more pharmaceutically acceptable rate-controlling polymers, which composition retains at least 80% of the potency of lacosamide or salts thereof in the said pharmaceutical composition after storage for three months at 40° C and 75% relative humidity.
Suitable dosage form comprises one or more of tablets, multilayered tablets, capsules, pellets, granules, spheroids, beads, minitablets in capsule, pellets in capsule, granules in capsule, powder. Further the powder or granules can be suspended to give a pharmaceutically acceptable oral suspension.
The extended release composition of lacosamide or its salt is preferably developed into dosage forms such as matrix-tablets/granules/pellets, coated tablets/granules/pellets or multiple unit particles which can be filled into capsules or compressed to. form tablets. In an embodiment, the extended release composition is not particularly limited as long as it is an oral preparation. For example, tablets, granules, fine granules, pellets, mini/micro tablets, capsules and the like can be manufactured in the present invention. Capsules can be packed with one or more tablets, granules or fine granules based on the matrix type extended release preparation according to the present invention. For example, hard capsules can be packed with multiple small-diameter mini-tablets based on the matrix type extended release preparation, or with the aforementioned granules or fine granules based on the matrix type extended release preparation, or with both tablets based on the matrix extended release preparation and granules or fine granules based on the matrix type extended release preparation. The matrix type extended release preparation can also be given a film coating as necessary.
In an embodiment, the extended release pharmaceutical composition in accordance with the present invention comprises multiple-unit particles comprising lacosamide or salts thereof and one or more pharmaceutically acceptable rate- controlling polymers.
In a further embodiment, the extended release pharmaceutical composition comprises multiple-unit particles comprising lacosamide or salts thereof coated with one or more pharmaceutically acceptable rate-controlling polymers.
In a further embodiment, the extended release pharmaceutical composition comprises multiple-unit particles comprising matrix of lacosamide or salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers, and optionally said multiple-unit particles are further coated with one or more rate- controlling polymers.
In a further embodiment, the extended release pharmaceutical composition comprises multiple-unit particles comprising inert core made up of water soluble material (e.g. lactose) or water insoluble material (e.g. microcrystalline cellulose) coated with consecutive or alternate layers of lacosamide and one or more rate- controlling polymer/s.
The extended release composition can also be given a film coating as necessary. It should be noted that the presence or absence of a hydrophilic film coating on the extended release preparation according to the present invention has very little effect on the dissolution profile of memantine or salt thereof. The 'non-functional coating' or 'film coating' may comprise polymers like hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, copolymer of vinyl pyrrolidone and vinyl acetate; plasticizers like polyethylene glycol, triacetin, dibutyl sebecate and diethyl tartrate; opacifying agents like titanium dioxide and talc; and coloring agents. Examples of such nonfunctional coats are commercially available Opadry® compositions.
The pharmaceutical compositions as described herein may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet or dry granulation, slugging, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion-spheronization, spray drying and solvent evaporation.
In a further embodiment, the process of manufacturing an extended release pharmaceutical composition of lacosamide or salts thereof in accordance with the present invention comprises- providing a matrix and/or coated core comprising lacosamide or salts thereof, one or more rate-controlling polymer/s and one or more pharmaceutically acceptable excipients.
In an embodiment, the extended release compositions may be prepared by mixing and granulating lacosamide or salts thereof with one or more rate-controlling polymers along with one or more pharmaceutically acceptable excipients to form granules. The granules can be dried. The dried granules can be milled, mixed with other pharmaceutically acceptable excipients, lubricated and formulated into suitable dosage form. Further, the dosage form can be coated with one or more rate-controlling polymers.
In a further embodiment, the process of preparing extended release pharmaceutical composition comprising multiple-unit particles, which process comprises steps of-
(a) coating inert core made up of water soluble (e.g. lactose or sugar) or water insoluble material (e.g. microcrystalline cellulose) with lacosamide or salts thereof with one or more rate-controlling polymer to form drug coated pellets,
(b) optionally providing one or more layer of non-functional coating or functional coating over the drug coated pellets,
(c) filing the pellets prepared in step (b) in hard gelatin capsules. The extended release pharmaceutical composition comprising lacosamide or salts thereof further may comprise additional anticonvulsant agent, which can be selected from one or more active agent/s selected from therapeutic category of antipsychotic agents, anticonvulsants and antidepressant agents, typical antipsychotics and atypical antipsychotics.
The pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.
Suitable fillers may include one or more of microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols_such as mannitol, sorbitol, erythritol and the like.
Suitable disintegrants may include one or more of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross- linked polyvinylpyrrolidone and the like.
Suitable binders may include one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like.
Suitable examples of plasticizers include, but not limited to glycerin fatty acid esters; triethyl citrate; propylene glycol; polyethylene glycol and the like.
Suitable lubricants and glidants may include one or more of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid,.hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; and the like
In a further embodiment, the invention provides a method for treating partial onset seizures in patients with epilepsy and/or preventing visual disturbance or PR prolongation, wherein method comprises administering an extended release pharmaceutical composition of lacosamide or salts thereof.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1
Table 1
Figure imgf000012_0001
Procedure: Lacosamide, hydroxypropyl cellulose, lactose monohydrate were mixed and granulated with isopropyl alcohol. Granules were dried and mixed with lactose anhydrous, talc, magnesium stearate, and colloidal silicon dioxide and the compressed into tablets using suitable tooling.
Table 2: Dissolution data
Figure imgf000012_0002
Table 2 provides dissolution data for lacosamide tablet prepared as per Example 1. For determination of drug release rate, USP Type I apparatus (lOOrpm) was used wherein 900mf of water and 0.1N HC1 was used as medium. Example 2
Table 3
Figure imgf000013_0001
Procedure: Lacosamide, hydroxypropyl cellulose (HXF), hydroxypropyl methylcellulose, lactose monohydrate were mixed and granulated with isopropyl alcohol. Granules were dried and mixed with lactose anhydrous, talc, magnesium stearate, and colloidal silicon dioxide and then compressed into tablets using suitable tooling.
Table 4: Dissolution data
Figure imgf000013_0002
Table 4 provides dissolution data for lacosamide tablet prepared as per Example 2. For determination of drug release rate, USP Type I apparatus (lOOrpm) was used wherein 900ml of water was used as medium.
Example 3
Table 5
Sr. No. Ingredients % w/w
1 Lacosamide 30-60
2 Hydroxypropyl cellulose (HXF) 5-50
3 Lactose monohydrate 10-90 4 Lactose anhydrous 5-20
5 Talc 0.1 -5
6 Magnesium stearate 0.1-5
7 Colloidal silicon dioxide 0.1 -5
8 Isopropyl alcohol Q. S.
Procedure: Lacosamide, hydroxypropyl cellulose (HXF), lactose monohydrate were mixed and granulated with isopropyl alcohol. Granules were dried and mixed with lactose anhydrous, talc, magnesium stearate, and colloidal silicon dioxide and then compressed into tablets using suitable tooling.
Table 6: Dissolution data
Figure imgf000014_0001
Table 6 provides dissolution data for lacosamide tablet prepared as per Example 3. For determination of drug release rate, USP Type I apparatus ( lOOrpm) was used wherein 900ml of water was used as medium.
Example 4
Table 7
Figure imgf000014_0002
Procedure: Lacosamide, hydrogenated castor oil, and hydroxypropyl cellulose were mixed and granulated with isopropyl alcohol and water. Granules were dried and mixed with lactose anhydrous, talc, and magnesium stearate and then compressed into tablets using suitable tooling.
Table 8: Dissolution data
Table 8 provides dissolution data for lacosamide tablet prepared as per Example 4. For determination of drug release rate, USP Type I apparatus (lOOrpm) was used wherein 900mf of water and 0. IN HCI was used as medium.
Example 5
Table 9
Figure imgf000015_0002
Procedure: Lacosamide, hydrogenated castor oil, and hydroxypropyl cellulose were mixed and granulated with isopropyl alcohol and water. Granules were dried and mixed with lactose anhydrous, talc, and magnesium stearate and then compressed into tablets using suitable tooling.
Table 10: Dissolution data
Water (UN HCI
Time (hr)
(% Drug release) (% drug release)
0.5 23.4 20.3
1 33.4 32.8
2 45.1 46.0 3 54.4 56.1
4 61.7 63.2
6 72.4 74.9
8 80.5 82.9
10 88.1 90.2
12 92.2 95
14 96.4 98.4
Table 10 provides dissolution data for lacosamide tablet prepared as per Example 5. For determination of drug release rate, USP Type I apparatus (lOOrpm) was used wherein 900mf of water and 0. IN HCI was used as medium.
Example 6
Table 11
Figure imgf000016_0001
Procedure:
Lacosamide and lactose monohydrate were mixed and granulated using binder solution of hydroxypropyl methylcellulose in isopropyl alcohol and water. Granules were dried and lubricated with talc, magnesium stearate, and colloidal silicon dioxide and the compressed into tablets using suitable tooling.
Dispersion of ammoniomethacrylate copolymers type A, type B, triethyl citrate, talc and coloring agent was sprayed onto core tablets in a suitable coating pan to yield coated tablets. Table 12: Dissolution data
Figure imgf000017_0001
Table 12 provides dissolution data for lacosamide tablet prepared as per Example 6. For determination of drug release rate, USP Type I apparatus (lOOrpm) was used wherein 900mf of water was used as medium.
Example 7
Table 13
Figure imgf000017_0002
Procedure: Lacosamide, hydroxypropyl cellulose (HXF), lactose monohydrate were mixed and granulated with isopropyl alcohol. Granules were dried and mixed with lactose anhydrous, talc, magnesium stearate, and colloidal silicon dioxide and then compressed into tablets using suitable tooling. Dispersion of ammoniomethacrylate copolymers type A, type B, triethyl citrate, talc and coloring agent was sprayed onto core tablets in a suitable coating pan to yield coated tablets. Table 14: Dissolution data
Figure imgf000018_0001
Table 14 provides dissolution data for lacosamide tablet prepared as per Example 6. For determination of drug release rate, USP Type I apparatus (lOOrpm) was used wherein 900mf of water was used as medium.
Table 15: Stability Data of Example 1
Figure imgf000018_0002

Claims

We Claim:
1. An extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients.
2. The extended release pharmaceutical composition of claim 1 , wherein the rate- controlling polymer is selected from one or more of hydrophilic polymer and/or hydrophobic polymer.
3. The extended release pharmaceutical composition of claim 2, wherein the hydrophilic polymer is selected from one or more of cellulosic polymers/copolymers or its derivatives including methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose; polyacrylates, methyl acrylates, polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols.
4. The extended release pharmaceutical composition of claim 2 or 3, wherein the hydrophilic polymer is hydroxypropyl methylcellulose, hydroxypropyl methylcellulose or mixture thereof.
5. The extended release pharmaceutical composition of claim 2, wherein the hydrophobic polymer is selected from one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methyl acrylates, acrylate copolymers and phthalate compolymers.
5. The extended release pharmaceutical composition of claim 2 or 5, wherein the hydrophilic polymer is hydrogenated vegetable oil.
6. The extended release pharmaceutical composition of claim 1, wherein the amount of rate-controlling polymer ranges from about 5% w/w to about 75% w/w of the composition. 7. The extended release pharmaceutical composition of claim 1, wherein the ratio of amount of lacosamide or salts thereof to rate-controlling polymer ranges from 1 : 10 to 10: 1.
8. The extended release pharmaceutical composition of claim 1, wherein the composition retains at least 80% of the potency of lacosamide or salts thereof after storage for 3 months at 40° C /75% RH.
9. A matrix-type extended release pharmaceutical composition comprising lacosamide or salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers.
1 1. An extended release pharmaceutical composition comprising multiple-unit particles comprising lacosamide or salts thereof and one or more pharmaceutically acceptable rate-controlling polymers.
12. The extended release pharmaceutical composition of claim 1, wherein said comprises a core of lacosamide or salts thereof coated with one or more rate-controlling polymers. 13. The extended release pharmaceutical composition of claim 1, wherein said composition exhibits a dissolution profile of lacosamide or salts thereof such that at least 80% of lacosamide or salt thereof is released from about 8 hour to about 24 hour after administration. 14. The extended release pharmaceutical composition of claim 1, wherein said composition is suitable for once daily administration.
15. The extended release pharmaceutical composition of claim 1, wherein said composition exhibits no significant difference in both rate and extent of absorption of lacosamide or salt thereof as compared to immediate release formulation of lacosamide marketed under trade name Vimpat® administered twice daily.
16. A process for preparing an extended release pharmaceutical composition of claim 1, which process comprises mixing lacosamide or salts thereof with one or more rate- controlling polymers optionally with other pharmaceutically acceptable excipients and forming the mixture thus obtained into pharmaceutical dosage form.
17. A process of manufacturing the extended release pharmaceutical composition of lacosamide or salts thereof comprising-
(a) mixing lacosamide or salt thereof with one or more pharmaceutically acceptable rate-controlling polymer/s optionally with one or more pharmaceutically acceptable excipients
(b) granulating or compression molding of above mixture to form granules, pellets, tablets and minitablets.
18. The extended release pharmaceutical composition of claim 1, wherein said composition exhibits a dissolution profile of lacosamide or salts thereof in water or simulated gastric fluid such that at least 10% of lacosamide is released after 2 hours, at least 20% of lacosamide is released after 4 hours, at least 40% of lacosamide is released after 8 hours, at least 60% lacosamide is released after 10 hours, and at least 80% lacosamide is released within 24 hours.
19. A method for treating partial onset seizures in patients with epilepsy and/or preventing visual disturbance or PR prolongation, wherein said method comprises administering an extended release pharmaceutical composition of lacosamide or salts thereof comprising one or more pharmaceutically acceptable rate-controlling polymers and one or more pharmaceutically acceptable excipients.
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