Field of the Invention:
The present invention relates to a modified release formulation of antiepileptic drug. The
formulation of the present invention comprises lacosamide or pharmaceutically acceptable
salts, esters, metabolites, prodrugs or enantiomers thereof and modified release polymer.
Background of the Invention:
The term epilepsy is derived from a Greek word meaning a condition of being seized or
overcome. The term epilepsy designates a group of central nervous system disorders
having in common the occurrence of sudden and transitory episodes of abnormal behavioral
symptoms of motor sensory, autonomic or psychic origin. Epilepsies have a definite onset
and ending, and they usually are of short duration.
Epileptic seizures are mainly of two types: partial seizures and generalized seizures. Partial
seizures can again be of three type; i.e. simple partial, complex partial and partial with
secondarily generalized tonic clonic seizure. Generalized seizures are classified as absence
seizure, myoclonic seizure and tonic-clonic seizure. Anti-epileptic drug are vital in preventing
fits for people with epilepsy, thereby greatly enhancing quality of life.
Based on their mechanism of action, anti-epileptic drugs can be classified as sodium
channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers,
glutamate blockers, carbonic anhydrase inhibitors etc.
Drugs such as acetazolamide, carbamazepine, clobazam, clonazepam, ethosuximide,
gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital (phenobarbitone),
phenytoin, pregabalin, primidone, rufinamide, sodium valproate, tiagabine,
topiramate, valproic acid, vigabatrin, zonisamide, valpromide, divalproex sodium,
gabapentin, felbamate, fosphenytoin and the like are used for the treatment of epilepsy.
Anti-epileptic drugs (AEDs) are also promising agents for the prevention of migraine and
other head pain. Migraine and epilepsy share several clinical features and respond to many
of the same pharmacological agents, suggesting that similar mechanisms may be involved
in their pathophysiology.
The most common side effects associated with epilepsy medicines are drowsiness,
irritability, nausea, rash, and clumsiness. Some drugs produce changes in emotions,
memory or behavior, or affect learning. Modified release formulations of anti-epileptic drugs
provides reduction in the above mentioned side effects, increased patient compliance,
avoids a typical peak-valley plasma concentration profile and ultimately reduction in the
precipitation of adverse effects especially of a drug with a narrow therapeutic index
whenever overmedication occurs.
Lacosamide, marketed as Vimpat®, is approved in US for the treatment of partial-onset
seizure in patient with epilepsy aged 17 years and older. The lacosamide may be used for
the treatment or prophylaxis of migraine, fibromyalgia syndrome, osteoarthritis, post herpetic
neuralgia and painful diabetic neuropathy. Chemically lacosamide is (2R)-2-(acetylamino)-
3-methoxy-N-(phenylmethyl)propanamide, R-enantiomer is at least 10-fold more active than
the S-enantiomer. US Pat. No. 5,654,301 discloses aminoacid derivative, lacosamide
eXhibiting anticonvulsant properties. RE 38,551 discloses the novel enantiomeric
compounds one of which is lacosamide.
Vimpat® is approved for oral or intravenous administration. Lacosamide for oral use has the
initial dose of 50 mg twice daily (100 mg per day). It can be increased at weekly intervals by
100 mg/day (two divided doses) up to the recommended maintenance dose of 200 to 400
mg/day, based on individual patient response and tolerability. The marketed formulation
Vimpat® is an immediate release formulation for BID administration
The side effect associated with lacosamide is similar to other epileptics as dizziness, ataxia,
vomiting, diplopia, nausea, vertigo and vision blurred.
There exists a need for modified release formulation of lacosamide which controls the
release of lacosamide in such a manner that therapeutically effective concentration is
maintained in the blood for an extended period of time keeping the drug concentration in the
blood substantially constant. The use of modified release formulations of lacosamide would
improve patient compliance as it reduces the numbers of dosages to be taken per day.
With the modified release formulation, the therapy may be continued without interrupting the
sleep of the patient, which is of special importance when treating an epileptic patient to
prevent nocturnal seizures, or patients with pain who experience severe pain on awakening,
as well as for debilitated patients for whom an uninterrupted sleep is essential.
Thus the modified release formulation of lacosamide would provide a modified release of
lacosamide with minimal Cmax to Cmin peak to trough variation over a period of at least 12
hrs. It is preferred that the modified release formulation of lacosamide is capable of
maintaining a substantially constant plasma level of lacosamide for at least 12 hrs.
Summary of the Invention:
In one embodiment, the modified release formulation of lacosamide comprises lacosamide
and modified release polymer.
In other embodiment, the modified release formulation of lacosamide further comprises core
comprising lacosamide and modified release coating.
In another embodiment, the modified release formulation futher comprises:
(i) a core comprising non-pareil seed;
(ii) coating the non-pareil seed with lacosamide; and
(iii) modified release coating.
In further embodiment, the modified release formulation of lacosamide releases not more
than about 25% of lacosamide within 1 hour, from about 30% to about 70% of lacosamide
within 4 hour and not less than about 75% of lacosamide within 12 hours when tested
according to USP type 1 dissolution apparatus at 100rpm and 37"C temperature in 900ml of
0.1N HCI.
In further embodiment, the modified release formulation compnslng lacosamide and
modified release polymer, said modified release formulation administered as a single dose
provides an invivo plasma profile selected from:
(i) Mean Tmax of about 5 or more hours, or
(ii) Mean Cmax of less than about 4600 ng/ml, or
(iii) Mean AUCO•72 of more than about 78500 ng . hr/ml
Brief Description of the Drawing:
FIG. 01 is a graph depicts the dissolution profile in 0.1N HCI of the formulations as
described in Example 03.
FIG. 02 is a graph depicts the mean plasma concentration-time profiles of lacosamide
following a single dose of the formulation (00) in Example 3 versus 100mg of the
commercially available immediate release tablet (VIMPA~).
Detailed Description of the Invention:
The invention provides a modified release formulation of antiepileptic drug preferably
lacosamideand modified release polymer.
The antiepileptic drug includes sodium channel blockers, calcium current inhibitors, gammaaminobutyric
acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors
and any other drug which has similar action.
The antiepileptic drug can be selected from the group consisting of lacosamide;
acetazolamide; carbamazepine; clobazam; c1onazepam; ethosuximide; gabapentin;
lamotrigine; levetiracetam; oxcarbazepine; phenobarbital (phenobarbitone); phenytoin;
pregabalin; primidone; rufinamide; sodium valproate; tiagabine; topiramate; valproic acid;
vigabatrin; zonisamide; valpromide; divalproex sodium; gabapentin; felbamate;
fosphenytoin; and combination thereof. Other drugs which have anti epileptic or antimigraine
activity are also within the scope of the invention. The preferred antiepileptic drug is
lacosamide.
As used herein the term "Iacosamide" refers to N2-acetyl-N-benzyl-D-homoserinamide
including its Rand S enantiomers and racemic mixtures or pharmaceutically acceptable
salts, estres, prodrugs or metabolites. The R enatiomer of N2-acetyl-N-benzyl-Dhomoserinamide
is the preferred enantiomer and the marketed immediate release
preparation Vimpat® contains the R enantiomer. The modified release formulation
preferably contains between 10-1000mg of lacosamide. It has been known that
pharmacokineticsof lacosamide is dose proportional at the therapeutic range.
The term "formulation" or "composition" as used herein refers to the drug in combination
with pharmaceutically acceptable excipients. This includes orally administrable formulations
as well as formulations administrable by other means.
"Modified release formulation" as used herein means a pharmaceutical formulation which
releases the drug substance at a slower rate than from an immediate release formulation.
The term modified release formulation can be used interchangeably with prolonged release
formulation, programmed release formulation, timed release formulation, extended release
formulation, site specific release formulation, sustained release formulation, controlled
release formulation, slow release formulation, delayed release formulation, osmotic dosage
form, bioadhesive formulation, orally disintegrating modified release formulation and other
such dosage forms.
The modified release formulation is preferably administered once a day (QD).
"Pharmaceutically acceptable" is meant a carrier comprised of a material that is not
biologically or otherwise undesirable.
The term "therapeutic effective concentration" is used throughout the specification to
describe concentration of lacosamide which is therapeutically effective in treatment and
prophylaxis of diseases where lacosamide is effective.
The term "relative bioavailability" herein denotes AUC for a specific orally administered
composition expressed as a percentage of AUC for an orally administered dosage form of
the active ingredient at the same dosage rate.
The terms "AUCO_72" herein mean the area under the curve relating blood plasma
concentration to time after administration from 0 to 72 hours, as determined using the linear
trapezoidal rule, and are expressed in units of (ng . hIm I).
The term "AUCo_oo" herein means the area under the curve relating blood plasma
concentration to time from time 0 hours to infinity, and is expressed in units of (ng . h/ml).
The term "AUCo_;' herein means area under the blood plasma concentration to time curve
from time zero to time tau over a dosing interval at steady state, where tau is the length of
the dosing interval, and is expressed in units of (ng . hIm I).
The term "Cmax" herein means the maximum observed blood plasma concentration or the
maximum blood plasma concentration calculated or estimated from a concentration to time
curve, and is expressed in units of nglml.
The term "Cmin"herein means the minimum observed blood plasma concentration or the
maximum blood plasma concentration calculated or estimated from a concentration to time
curve, and is expressed in units of ng/ml.
The term "Cavg"as used herein, means the plasma concentration of the drug within the
dosing interval, and is calculated as AUC/dosing interval, and is expressed in units of ng/ml.
The term "Tmax"herein means the time after administration at which Cmaxoccurs, and is
expressed in units of hours (h).
The term "single dose" means that the human patient has received a single dose of the drug
formulation and the drug plasma concentration has not achieved steady state.
The term "steady state" means that the blood plasma concentration curve for a given drug
does not substantially fluctuate after repeated doses to dose of the formulation.
The term "Degree of Fluctuation" is expressed as (Cmax- Cmin)/Cavg.
The term "bioequivalence" means the absence of a significant difference in the rate and
extent to which the active ingredient or active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug action when administered
at the same molar dose under similar conditions in an appropriately designed study.
The modified release formulation includes tablets, coated tablets, layered tablets, granules,
powders, microparticles, capsules which may be hard gelatin or soft gelatin, caplets,
sachets, pellets, spheroids, mini-tablets, beads, microcapsules and pills.
One embodiment discloses the modified release dosage form of lacosamide comprising
lacosamide and modified release polymer.
Other embodiment discloses the modified release formulation of lacosamide and modified
release polymer which provides therapeutically effective concentration of lacosamide for a
period of at least 8 hrs preferably 24 hrs or more.
Another embodiment discloses the modified release formulation which releases the active
ingredient lacosamide - over a period of at least 4 hrs, preferably at least 8 hrs and more
preferably of at least 12 hrs.
In further embodiment, the modified release formulation comprising lacosamide and
modified release polymer, said modified release formulation administered as a single -dose
provides an invivo plasma profile selected from:
(i) Mean Tmax of about 5 or more hours, or
(ii) Mean Cmax of less than about 4600 ng/ml, or
(iii) Mean AUCO_72 of more than about 78500 ng . hr/ml
Lacosamide is administered as a single dose in the dose range of 50 to 800mg,
preferably 100 to 600mg and more preferably in the dose of 200mg.
Further it is contemplated that at given plasma level of lacosamide per specified dose will be
directly proportional to other doses of lacosamide. Such proportional dose and plasma
levels are contemplated to be within the scope of the claimed invention.
The modified release polymer may be selected from hydrophlic polymer, hydrophobic
polymer or wax. The hydrophilic polymer may be selected from the group consisiting of
cellulose derivatives such as methyl cellulose, hydroxypropyl methylcellulose
(hYPromellose), hydroxyethyl cellulose, hydroxypropyl cellulose hydroxyethyl
methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose; vinyl
pyrrolidone polymers such as polyvinylpyrrolidone and copolymers of vinyl pyrrolidone and
Vinylacetate; alkylene oxide such as polyethylene oxide; polysaccharides such as chitosan;
gellan; xanthan gum; gums of plant, animal, mineral or synthetic origin; and alginic acid
derivatives such as alginic acid and its physiologically acceptable salts such as sodium,
potassium or calcium.
Hydrophobic polymer may be selected from the group consisting of ethyl cellulose;
cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate
trimellitate; polyvinylacetate phthalate; hydroxypropylmethylcellulose phthalate;
hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate); poly (vinyl
acetate); poly vinyl alcohols; and polyacrylamide derivatives.
Wax may be selected from the group consisting of glycerol palmitostearate; beeswax;
glycowax; castor wax; carnauba wax; glycerol monostearate; stearyl alcohol; glycerol
behenic acid ester; cetyl alcohol; natural and synthetic glycerides; waxes; fatty acids; and
hydrogenated vegetable oil.
In one embodiment the modified release polymer used in the modified release formulation
may be bioadhesive.
The bioadhesive polymers may be selected from the group consisting of proteins (e.g.,
hydrophilic proteins) such as pectin, zein, modified zein, casein, gelatin, gluten, plasma
albumin and collagen; chitosan; oligosaccharides; polysaccharides such as cellulose,
dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum arabic,
hyaluronic acid, polyhyaluronic acid, alginic acid and sodium alginate; 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 or copolymers or mixtures thereof.
Combination of modified release polymers is also included within the scope of the invention.
The amount of modified release polymers may range from about 10-90%.
The modified release formulation may further contain pharmaceutically acceptable
excipients such as binders; diluents; lubricants; disintegrating agents; glidants; stabilizers;
and surface active agents.
The binders may be selected from potato starch; modified starch; gelatin; wheat starch; corn
starch; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropylmethyl cellulose (Hypromellose), ethyl cellulose and sodium carboxy
methyl cellulose; natural gums such as acacia, alginic acid and guar gum; liquid glucose;
dextrin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; poly vinyl alcohol; poly-
N-vinyl amide; polyethylene glycol; gelatin; poly propylene glycol; tragacanth; hydrogenated
vegetable oil; castor oil; paraffin; higher aliphatic alcohols; higher alphatic acids; long chain
fatty acids; fatty acid esters; and wax-like materials such as fatty alcohols, fatty acid esters,
fatty acid glycerides, hydrogenated fats, hydrocarbons, nor- 50 mal waxes, stearic acid and
stearyl alcohol. The amount of binder present can vary from about 0.1% to about 25% by
weight of the tablet dry weight, preferably about 0.5% to about 10%.
The diluent may be selected from pharmaceutically acceptable inert fillers such as
microcrystalline cellulose; lactose; dibasic or tribasic calcium phosphate; saccharides
confectioner's sugar; compressible sugar; dextrates; dextrin; dextrose; fructose; lactitol;
mannitol; sucrose; starch xylitol; sorbitol; talc; calcium carbonate; or calcium sUlphate. The
diluent is preferably used in an amount of about 10 to 90% by weight.
The disintegrating agent may be selected from cross-linked polymers such as crospovidone;
starch or modified starch such as sodium starch glycolate; clays such as bentonite or
veegum; celluloses or cellulose derivatives or crosslinked cellulose such as croscarmellose
sodium; or resins such as polacrillin potassium.
The lubricant may be selected from Mg, AI or Ca or Zn stearate; polyethylene glycol; glyceryl
behenate; glyceryl monosterate; mineral oil; sodium stearyl fumarate; stearic acid;
hydrogenated vegetable oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine;
polyethylene glycol; ethylene oxide polymers; or colloidal silica.
The glidant may be selected from magnesium trisilicate; powdered cellulose; starch; talc and
tribasic calcium phosphate; calcium silicate; magnesium silicate; colloidal silicon dioxide; or
silicon hydrogel.
The modified release formulation may optionally contain a surface active agent. The
preferred surface active agent may be selected from a group consisting of fatty acid; olefin;
alkylcarbonyl; silicon elastomer; sulfate ester; petty alcohol sulfate; sulfate pete and oil;
sulfonic acid-base; fat sulfonate; alkylaryl sulfonate; ligmin sulfonate; phosphoric acid ester;
polyoxyethylene; polyoxyethylene caster oil; polyglycerol; polyol; imidazol; altanolamine;
hetamine; sulfobecamine; phosphotide; polyoxyethylene-sorbitan fat acid ester (Tween);
and sorbitan ester (Span).
The osmotic agents may be selected from sodium chloride; potassium chloride; magnesium
sulfate; magnesium chloride; sodium sulfate; lithium sulfate; urea; inositol; sucrose; lactose;
glucose; sorbitol; fructose; mannitol; dextrose; magnesium succinate or potassium acid
phosphate.
In one of the embodiment the modified release formulation comprises lacosamide and
modified release polymer which may optionally coated.
The coating may be modified release coating which may modify the release of drug from
modified release formulation or coating which does not alter the release of drug from the
modified release formulation.
Commercially available, ready-to-coat preparations, sold under various brand names such
as various grades of Opadry®. Opadry® is a film coating system comprising hypromellose,
polyethylene glycol and titanium dioxide which does not alter the release of drug from
modified release formulation may also be used.
Examples of modified release coating include functional coating; moisture barrier coatings;
enteric polymeric coatings; sustained release coating; and the like.
In one embodiment the modified release formulation further comprises core comprising
lacosamide and modified release coating.
In other embodiment the modified release formulation comprises a core comprising
lacosamide and modified release coating which provides therapeutically effective
concentration of lacosamide for a period of at least 8 hrs preferably 24 hrs or more.
The core may further comprise pharmaceutically acceptable excipients.
In another embodiment, the modified release formulation further comprises:
(i) a core comprising non-pareil seed;
(ii) coating the non-pareil seed with lacosamide; and
(iii) modified release coating
In another embodiment, the modified release formulation further comprises:
(i) a core comprising non-pareil seed;
(ii) coating the non-pareil seed with lacosamide; and
(iii) modified release coating
which provides therapeutically effective concentration of lacosamide for a period of at least
8 hrs preferably 24 hrs or more.
The non-pareil seed may be selected from sugar spheres, microcrystalline cellulose or other
inert material.
The modified release coating comprises of modified release polymer and other
pharmaceutically acceptable excipients. The modified release polymer includes hydrophilic
polymer, hydrophobic polymer or wax as disclosed above.
The modified release coating composition may comprise of cellulosic polymer selected form
hydroxypropyl cellulose (HPC); hydroxyethyl cellulose; hydroxypropyl methylcellulose
(hypromellose); methyl cellulose; ethyl cellulose; cellulose acetate; cellulose acetate
butyrate; cellulose acetate phthalate; cellulose acetate succinate; cellulose acetate
propionate; cellulose acetate trimellitate; hydroxypropylmethyl cellulose phthalate;
hydroxypropylmethyl cellulose succinate; hydroxypropylmethyl cellulose acetate succinate;
cellulose acetate succinate butyrate; cellulose acetate succinate propionate;
carboxymethylcellulose sodium, cellulose butyrate; and mixtures thereof; pH-independent
acrylates such as Eudragit RS, Eudragit RL and the like; pH-dependent polymers such as
poly(methacrylic acid, methylmethacrylate) 1:1, poly(methacrylic acid, ethylacrylate) 1:1,
poly(methacrylic acid, methylmethacrylate) 1:2, and the like or waxes such as polyethylene
glycol.
The modified release coating may be aqueous, nonaqueous or combination of the two.
If desired, the permeability of the modified release coating may be adjusted by blending of
two or more excipients. The porosity of the modified release coating may be modified by
using pore forming agents. The pore forming agents may be selected from crystals of
sucrose; mannitol; sorbitol; or salts such as sodium chloride or potassium chloride.
The modified release coating composition may further include other pharmacetically
acceptable excipients such as plasticizer, solvent system (Le., water), a colorant to provide
elegance and product distinction. Color may be added to the solution of the therapeutically
active agent instead, or in addition to the overcoat. Suitable ingredients for providing color to
the formulation include titanium dioxide and color pigments, such as iron oxide pigments.
The incorporation of pigments, may, however, increase the retard effect of the coating.
Alternatively, any suitable method of providing color to the formulations of the present
invention may be used.
The plasticizer may be selected from the group consisting of one or more of polyethylene
glycol; triethyl citrate; triacetin; diethyl phthalate; dibutyl stearate; dibutyl sebacate; oleic
acid; alcohol; mineral oil; castor oil; lanolin; petrolatum; propylene glycol; and glycerol.
The modified release formulation may be manufactured by various methods known in the art
such as by dry granulation, wet granulation, melt granulation, direct compression, double
compression, extrusion spheronization, layering and the like. Compaction of the blend into
coprimate may be carried out using a slugging technique or roller compaction. The milling of
the granules may be carried out according to conventional milling methods.
The process of wet granulation includes aqueous or non-aqueous solvents.
The coating operation may be conducted in standard equipment such as a fluid bed coater,
a wurster coater or a rotary bed coater.
The invention is not to be limited in scope by the specific embodiments described herein.
Indeed, various modifications of the invention in addition to those described herein will
become apparent to those skilled in the art from the foregoing description. Such
modifications are intended to fall within the scope of the appended claims.
Example 01:
Sr.No. Ingredients %w/w
1 Lacosamide 32.26
2 Polyethylene Oxide 24.19
3 Hypromellose 8.06
4 Mannitol 32.27
5 Colloidal silicon dioxide 1.61
6 Magnesium Stearate 1.61
Film Coating : 2 - 3 %
Procedure:
1. Sift all ingredients through suitable sieve
2. Blend and mix together Lacosamide, Polyethylene Oxide and Hypromellose in a
suitable blender.
3. Add Mannitol to Step 2 and mix till uniform blend is obtained.
4. Mix Step 3 with Colloidal silicon dioxide and lubricate with Magnesium Stearate for 5
minutes.
5. Compress the step 4 into tablet using suitable punch tooling.
6. Coat the tablets with coating solution either organic or aqueous or semiaqueous
solution.
Example 02:
Sr.No. Ingredients %w/w
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
Film Coating: 2 - 3 %
Procedure:
1. Sift all ingredients through suitable sieve.
2. Blend and mix together Lacosamide and Microcrystalline cellulose in a suitable
blender and load in RMG.
3. Dissolve and prepare a clear solution of Polyvinylpyrrolidone in solvent.
4. Granulate the Step 2 with the solution from step 3 and dry the granules in Dryer and
mill/size them by passing through suitable mesh.
5. Mix and blend the step 4 with Polyethylene Oxide, Hypromellose to form a uniform
blend.
6. Mix Step 5 with Colloidal silicon dioxide and lubricate with Magnesium Stearate for 5
minutes.
7. Compress the step 6 into tablet using suitable punch tooling.
8. Coat the tablets with coating solution either organic or aqueous or semiaqueous
solution.
Example 03:
Sr.No. Ingredients %w/w
1 Lacosamide 19.05
2 Hypromellose 28.57
3 Microcrystalline cellulose 23.81
4 Copovidone 23.81
5 Aerosil 2.86
6 Magnesium Stearate 1.90
7 Solvent a.s.
Procedure:
1. Sift Lacosamide, Hypromellose and Microcrystalline cellulose through 30# sieve.
2. Dissolve Copovidone in solvent.
3. Granulate step 1 with the solution of step 2.
4. Dry the granules at 45 ·C and then pass through 20# sieve.
5. Sift Microcrystalline cellulose, Crospovidone and Aerosil through 40# sieve.
6. Lubricate step 5 by using Mg-stearate passed through 60# sieve.
7. Compress step 6 by using suitable punch.
8. Coat the tablet of Step 7 by using Opadry coating solution (2-3% wt. Gain)
Example 04:
Sr.No. Ingredients %w/w
1 Lacosamide 33.33
2 Hydrogenated Vegetable Oil 8.33
3 Microcrystalline cellulose 34.17
4 Stearic acid 4.17
5 Polyethylene glycol 16.67
6 Solvent a.s.
7 Colloidal silicon dioxide 1.67
8 Magnesium Stearate 1.67
Film Coating: 2 - 3 %
Procedure:
1. Sift all ingredients through suitable sieve.
2. Add and melt Hydrogenated Vegetable Oil, Polyethylene glycol and Stearic acid in
preheated steam jacketed vessel at 60-70 DC and to this melted mass, add
Lacosamide and stearic acid under stirring, stop the heating and continue the stirring
for 30-45 min until a uniform mass is formed.
3. Cool the molten uniform mass to room temperature and mill the solidify mass in comill
using suitable sieve.
4. Mix and blend the step 3 with Microcrystalline cellulose for 5-10 minutes.
5. Mix Step 4 with Colloidal silicon dioxide and lubricate with Magnesium Stearate for 5
minutes.
6. Compress the step 5 into tablet using suitable punch tooling.
7. Coat the tablets with coating solution either organic or aqueous or semiaqueous
solution.
Example 05:
Sr.No. Ingredients %w/w
1st Layer
1 Lacosamide 20.00
2 Hypromellose 21.50
3 Microcrystalline cellulose 11.50
4 Copovidone 15.00
5 Aerosil 1.00
6 Magnesium Stearate 1.00
7 Solvent a.s.
IInd Layer
1 Polyethylene oxide 170.59
2 Sodium Chloride 76.47
3 Hypromellose 35.88
4 Hydroxypropyl cellulose 9.41
5 Red iron oxide 0.59
6 Magnesium Stearate 7.06
7 Solvent a.s.
Procedure:
First Layer
1. Sift Lacosamide, Hypromellose and Microcrystalline cellulose through 30# sieve.
2. Dissolve Copovidone in solvent.
3. Granulate step 1 with the solution of step 2.
4. Dry the granules at 45 ·C and then passed through 20# sieve.
5. Sift Crospovidone and Aerosil 200 through 40# sieve.
6. Lubricate step 5 by using Magnesium Stearate passed through 60# sieve.
Second Layer
1. Sift Polyethylene oxide, Sodium Chloride, Hypromellose, Hydroxypropyl cellulose
and Red iron oxide through 40# sieve.
2. Granulate step 1 by using solvent.
3. Dry the granUles at 45 ·C and then passed through 20# sieve.
4. Lubricate step 3 by using Magnesium Stearate passed through 60# sieve.
Compression
Compress both layers by using suitable punch
Coating:
Coat the compressed tablet by using Opadry coating solution (2-3% wt. Gain)
Example 06:
Sr.No. Ingredients %w/w
1 Lacosamide 32.26
2 Microcrystalline cellulose 28.23
3 Polyvinylpyrrolidone 4.03
4 Xanthum Gum 24.19
5 Hypromellose 8.06
6 Solvent a.s.
7 Colloidal silicon dioxide 1.61
8 Magnesium Stearate 1.61
Film Coating: 2 - 3 %
Procedure:
1. Sift all ingredients through suitable sieve
2. Blend and mix together Lacosamide and Microcrystalline cellulose in a suitable
blender and load in Rapid Mixer Granulator.
3. Dissolve and prepare a clear solution of Polyvinylpyrrolidone in solvent.
4. Granulate the Step 2 with the solution from step 3 and dry the granules in Dryer and
mill/size them by passing through suitable mesh.
5. Mix and blend the step 4 with Xanthum Gum, Hypromellose to form a uniform blend.
6. Mix Step 5 with Colloidal silicon dioxide and lubricate with Magnesium Stearate for 5
minutes.
7. Compress the step 6 into tablet using suitable punch tooling.
8. Coat the tablets with coating solution either organic or aqueous or semiaqueous
solution
Example 07:
Sr.No. Ingredients %w/w
1 Lacosamide 32.26
2 Microcrystalline cellulose 28.23
3 Polyvinylpyrrolidone 4.03
4 Sodium alginate 24.19
5 Hypromellose 8.06
6 Solvent a.s:
7 Colloidal silicon dioxide 1.61
8 Magnesium Stearate 1.61
Film Coating: 2 - 3 %
Procedure:
1. Sift all ingredients through suitable sieve.
2. Blend and mix together Lacosamide and Microcrystalline cellulose in a suitable
blender and load in Rapid Mixer Granulator.
3. Dissolve and prepare a clear solution of Polyvinylpyrrolidone in solvent.
4. Granulate the Step 2 with the solution from step 3 and dry the granules in Dryer and
mill/size them by passing through suitable mesh.
5. Mix and blend the step 4 with Sodium alginate, Hypromellose to form a uniform
blend.
6. Mix the blend of Step 5 with Colloidal silicon dioxide and lubricate with Magnesium
Stearate for 5 minutes.
7. Compress the step 6 into tablet using suitable punch tooling.
8. Coat the tablets with coating solution either organic or aqueous or semiaqueous
solution.
Example 08:
Sr.No. Ingredients %w/w
Drug loading
Spray solution/dispersion
1 Lacosamide 13.33
2 Hypromellose 6.66
3 Ethyl cellulose 26.66
4 solvent a.s.
5 Sugar Spheres/ Microcrystalline 53.33
Cellulose Spheres
Capsule fill Weight 100
Fill the drug loaded pellets in suitable size of capsule
Procedure:
1. Sift all ingredients through suitable sieve.
2. Dissolve and make a clear solution of Lacosamide, Hypromellose and Ethyl cellulose
in solvent under stirring.
3. Load Sugar / Microcrystalline Cellulose Spheres in Fluidized Bed Processor and
spray the solution from step 2.
4. Fill the capsule with drug-loaded pellets from step 3.
Example 09:
Sr.No. Ingredients %w/w
Drug loading
Spray solution/dispersion
1 Lacosamide 15.62
2 Hypromellose 15.62
3 Solvent a.s.
Extragranular
4 Sugar Spheres! Microcrystalline 62.5
Cellulose Spheres
Modified release coating with Eudragit
Fill the drug loaded pellets in suitable size of capSUle
Procedure:
1. Sift all ingredients through suitable sieve.
2. Dissolve and make a clear solution of Lacosamide and Hypromellose in solvent
under stirring.
3. Load Sugar ! Microcrystalline Cellulose Spheres in Fluidized Bed Processor and
spray the solution from step 2.
4. Dissolve Eudragit RL, Eudragit RS in solvent and add Dibutyl Sebacate.
5. Fill the above drug loaded pellets in suitable size of capsule.
Example 10:
Sr.No. Ingredients %w/w
1 Lacosamide 7.194
2 Microcrystalline cellulose 32.374
4 Hypromellose 32.373
5 Polyvinylpyrrolidone / Co-Povidone 3.597
6 Solvent Q.S.
7 Crospovidone 14.388
8 Microcrystalline cellulose 7.194
9 Colloidal silicon dioxide 1.438
10 Magnesium Stearate 1.438
Modified release coating coating with EUdragit : 3 - 4 %
Procedure:
1. Sift all ingredients through suitable sieve
2. Blend and mix together Lacosamide, Microcrystalline cellulose and Hypromellose in
a suitable blender and load in Rapid Mixer Granulator.
3. Dissolve and prepare a clear solution of Polyvinylpyrrolidone in solvent.
4. Granulate the Step 2 with the solution from step 3 and dry the granules in Dryer and
mill/size them by passing through suitable mesh.
5. Mix and blend the step 4 with Co-Povidone, Hypromellose and Microcrystalline
cellulose to form a uniform blend.
6. Mix Step 5 with Colloidal silicon dioxide and lubricate with Magnesium Stearate for 5
minutes.
7. Compress the step 6 into tablet using suitable punch tooling.
8. Coat the tablets with above modified release coating solution prepared by dissolving
Ammino-methacrylate co-polymer type A and type B, Dibutyl sebacaterrriethyl
citrate/Polyethylene glycol in an above mentioned solvent.
Example 11:
Sr.No. Ingredients %w/w
1 Lacosamide 7.1,9
2 Microcrystalline cellulose 32.37
3 Hypromellose 32.37
4 Polyvinylpyrrolidone I Co-Povidone 3.597
5 Solvent a.s.
6 Crospovidone 14.38
7 Microcrystalline cellulose 7.194
8 Colloidal silicon dioxide 1.438
9 Magnesium Stearate 1.438
Modified release coating with Eudragit : 7-8%
Procedure:
1. Sift all ingredients through suitable sieve.
2. Blend and mix together Lacosamide and Microcrystalline cellulose in a suitable
blender and load in Rapid Mixer Granulator.
3. Dissolve and prepare a clear solution of Polyvinylpyrrolidone in solvent.
4. Granulate the Step 2 with the solution from step 3 and dry the granules in Dryer and
mill/size them by passing through suitable mesh.
5. Mix and blend the step 4 with Co-Povidone, Hypromellose and Microcrystalline
cellulose to form a uniform blend.
6. Mix Step 5 with Colloidal silicon dioxide and lubricate with Magnesium Stearate for 5
minutes.
7. Compress the step 6 into tablet using suitable punch tooling.
8. Coat the tablets with modified release coating dispe'rsion prepared by Methacrylic
acid co-polymer dispersion, Triethyl citrate, Talc and water.
Example 12:
Dissolution study for lacosamide tablets of Example 03 :
The dissolution profile of the 200mg lacosamide tablets of Example 03 was carried out in
type 1 dissolution apparatus, basket, at 100rpm, at a temperature of about 3TC, in 900ml of
0.1N HCI and may release not more than about 25% of lacosamide within 1 hour, from
about 30% to about 70% of lacosamide is released within 4 hour and not less than about 75
% of lacosamide is released within 12 hours. The results of the in vitro dissolution profile
are set forth in Table: 01 and illustrated in FIG. 01
Table: 01
Dissolution profile of lacosamide 200mg modified release tablets of Example 03
Time (Hrs) Avg. % Drug Release
0 0
1 15
2 21.9
4 38.5
6 46.7
8 59.2
10 66.5
12 72.9
14 81.1
16 88.3
Example 13:
Clinical study for lacosamide tablets of Example 03:
A single dose study was conducted in healthy human volunteers to assess bioavailability of
lacosamide formulated as the 200 mg QD modified release tablets of Examples 3 by
comparison with a reference treatment with Vimpat® 100mg tablet BID (each tablet
containing lacosamide 100mg - one tablet each 12 hourly) manufactured for UCB, GA.
administered under fed conditions in healthy, adult, male, human subjects in a randomized
cross over study and to evaluate safety and tolerability of lacosamide when its absorption
profile is altered as in these modified release tablets.
The study design was open label. balanced, randomized, three treatment, three sequence.
three-period, single dose crossover bioequivalence study in 12 healthy, adult. male, human
sUbjects under fed conditions.
The pharmacokinetic parameters AUCo_72. AUCo.oo• Cmax, and Tmax were estimated during
the study.
Geometric mean plasma lacosamide concentrations over the 72-hour assessment period
are shown in FIG.02. The pharmacokinetic parameters calculated from mean plasma
lacosamide concentration-time profile are given in Table: 02.
Table: 02
Pharmacokinetic parameters (mean ± standard deviation)
Parameter Test (Lacosamide
200mg modified release
tablet (QD)- Example 3)
Reference (Vimpat®
100mg tablet(BID)
TIR (%)
AUCO-72 (ng .
hlml)
AUCo_ .. (ng . h/ml)
100606.90 ± 21882.72 102700.93± 25661.12 97.96
109263.99 ± 24438.17 113722.90 ± 27763.30 96.08
Cmax (ng Iml) 3799.61 ± 733.15
12.00
3631.46 ± 380.59 104.63
Tmax (h) 4.50
The relative bioavailability of the Example 3 formulation to Vimpat® was 97.96 % in terms of
AUCO-72 ratio.
The mean plasma lacosamide concentration profile shown in FIG. 02 clearly shows the
tablets of Example 3 effectively modified the release of lacosamide relative to the immediate
release tablet (Vimpat®)
We Claim:
1. A modified release formulation comprising lacosamide and modified release polymer.
2. The modified release formulation of claim 1, wherein the modified release polymer is
selected from the group consisting of hydrophilic polymer, hydrophobic polymer,
wax; and mixtures thereof.
3. The modified release formulation of claim 2, wherein the hydrophilic polymer is
selected from the group consisting of cellulose derivatives such as methyl cellulose,
hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxyethyl methylcellulose, carboxymethylcellulose and sodium
carboxymethylcellulose; vinyl pyrrolidone polymers such as polyvinylpyrrolidone and
copolymers of vinyl pyrrolidone and vinyl acetate; polysaccharides; gums of plant,
animal, mineral or synthetic origin; polysaccharide such as alginic acid derivatives;
chitosan, gellan and xanthan gum; alkylene oxide such as polyethylene oxide; and
mixtures thereof.
4. The modified release formulation of claim 2, wherein the hydrophobic polymer is
selected from the group consisting of ethyl cellulose; methacrylic acid derivatives;
cellulose acetate and its derivatives; poly vinyl alcohols and its derivatives;
polyacrylamide derivatives; and mixtures thereof.
5. The modified release formulation of claim 2, wherein the wax is selected from the
group consisting of glycerol palmitostearate; beeswax; glycowax; castor wax;
carnauba wax; glycerol monostearate; stearyl alcohol; glycerol behenic acid ester;
cetyl alcohol; natural and synthetic glycerides; waxes; fatty acids; hydrogenated
vegetable oil; and mixtures thereof.
6. The modified release formulation of claim 1, wherein the modified release
formulation further comprises core comprising lacosamide and modified release
coating.
7. The modified release formulation of claim 1, wherein the modified release
formulation further comprises:
(i) a core comprising non-pareil seed;
(ii) coating the non-pareil seeds with lacosamide; and
(iii) modified release coating
26
8. The modified release formulation of claim 1, wherein the modified release
formulation provides therapeutically effective concentration of lacosamide for a
period of at least 24 hrs.
9. The modified release formulation of claim 1, wherein the modified release
formulation of lacosamide releases not more than about 25% of lacosamide within 1
hour, from about 30% to about 70% of lacosamide within 4 hour and not less than
about 75% of lacosamide within 12 hours when tested according to USP type 1
dissolution apparatus at 100rpm and 3TC temperature in 900ml of 0.1 N HCI.
10. A modified release formulation comprising lacosamide and modified release polymer,
wherein the modified release formulation administered as a single dose provides an
invivo plasma profile selected from:
(i) Mean Tmax of about 5 or more hours, or
(ii) Mean Cmax of less than about 4600 ng/ml, or
(iii) Mean AUCO_72 of more than about 78500 ng . hr/ml
11. A modified release formulation of Claim 10, wherein the modified release formulation
is administered in dose range of 50 to 800mg of lacosamide.
12.A modified release formulation of Claim 11, wherein the modified release formulation
is administered in dose range of 100-600mg of lacosamide.
13. A modified release formulation of Claim 12, wherein the modified release formulation
is administered in dose of 200mg of lacosamide.
14. The modified release formulation of lacosamide SUbstantially as hereinbefore
described and exemplified.