CONTROLLED RELEASE PHARMACEUTICAL
COMPOSITIONS OF BRIVARACETAM
Field of the invention
The present invention relates to controlled release pharmaceutical compositions comprising
Brivaracetam or its pharmaceutically acceptable derivatives thereof.
Background of the invention
Epilepsy is a relatively common neurological condition affecting 0.4-1% of the world's
population (45-100 million people). For the general population there are approximately 20-70
new cases per 100,000 diagnosed each year with a 3-5% lifetime probability of developing
the disease.
Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked
seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or
synchronous neuronal activity in the brain. It is classified etiologically as symptomatic or
idiopathic with seizure manifestations that fall into three general categories: ) generalized
tonic-clonic, 2) absence or petit mal, and 3) complex partial. Symptomatic classification
indicates that a probable cause exists and a specific course of therapy to eliminate that cause
may be tried, whereas idiopathic indicates that no obvious cause can be found and may be
linked to unexplained genetic factors. Of the seizure categories, most people have only one
type of seizure, while about 30% have two or more types.
Currently, various drugs are available for the treatment of epilepsy or epileptic condition, and
commonly referred to as anticonvulsants or antiepileptics. Example of these drugs includes
carbamazepine, sodium valproate, phenytoin sodium, ethosuximide, clonazepam, diazepam,
nitrazepam, primidone, phenobarbitone, gabapentin, pregabalin, progabide, vigabatrin.
lamotrigine, topiramate and levetiracetam. These drugs are marketed in different dosage
forms such as conventional immediate release tablets, capsules and the like or controlled
release dosage forms in several geographies.
Most conventional oral drug products, such as tablets and capsules, release the active drug
immediately after oral administration over a shorter period of time, such as 60 minutes or
less to attain rapid systemic drug absorption and have quick onset of pharmacodynamic
effects. As immediate release drug products are absorbed into the body quickly, there will be
a sharp rise in blood levels. These 'peaks' may be associated with side effects such as
dizziness, drowsiness and lack of coordination. However, plasma drug concentration
declines, according to the drug's pharmacokinetic profile and eventually it falls below the
minimum effective plasma concentration (MEC), resulting in loss of therapeutic activity.
To maintain reasonably stable plasma concentrations, it is necessary to resort frequent
dosing. This leads to substantial fluctuations in the plasma concentration of the drug,
especially in chronic administration. Moreover, frequent dosing of immediate release drug
products results into inconvenience to the patient which leads to decreased patient
compliance.
To overcome disadvantage associated with immediate release drug products, a concerted
effort has been devoted to the discovery of controlled release drug products. Controlled
release drug products offer several advantages over immediate-release drug products of the
same drug. Controlled release allows sustained therapeutic blood levels of the drug for a
prolonged period of time and consistent clinical response in the patient. As in controlled
release drug products, the drug input rate is constant, the blood levels do not fluctuate which
leads to better patient convenience and patient compliance.
Brivaracetam is a n-propyl derivative of levetiracetam which has a molecular structure as
shown below
t has been studied for various potential indications, including epilepsy, neuropathic pain, and
essential tremors, among others. The drug interacts selectively with specific binding sites in
the brain.
n preclinical studies Brivaracetam showed affinity for synaptic vesicle protein 2.A (SV A).
Brivaracetam also has inhibitory activity at neuronal voltage-dependent sodium channels
whose abnormal function is understood to contribute to electrical discharges associated with
seizures.
Brivaracetam is effective in the treatment of epilepsy. Clinical trials evaluated the efficacy
and safety of Brivaracetam (5, 20, 50 and 150 mg per day) in the adjunctive treatment of
adult patients ( 16-65 years) with refractory partial onset seizures with or without secondary
generalization.
Pharmacokinetic studies shows that Brivaracetam is water soluble drug (700 mg /' ) with a -
half life of 7.6 t 1.7 hours and Cmax of 1.5 hours post dose {Maria et al. Pharmacokinetics
and Metabolism of l C-Brivaracetam, A Novel S V A Ligand in Health)' Subjects. American
Societyfor Pharmacology and Experimental Therapeutics: Oct 2001)
Brivaracetam has short half-life and high water solubility. These characteristics are ideal to
develop controlled release pharmaceutical compositions which invaiiabl) will offer various
advantages over conventional immediate release drug products such as constant therapeutic
plasma concentration of Brivaracetam over prolonged periods, reduced number of doses per
day or week, reduced adverse effects and improved patient compliance and convenience.
WO 2009/144286 discloses a pharmaceutical composition in the form of a tablet comprising
Brivaracetam and, as excipient within the core of the. tablet, 5% to 80% per weight of at least
one hydrophilic matrix agent, with respect to the total weight of the core of the tablet.
Hydrophilic polymer matrix systems are widely used to develop controlled pharmaceutical
compositions because of their flexibility to obtain a desirable drug release profile, costeffectiveness,
and broad regulatory acceptance. However, the drug release for extended
duration, particularly for highly water-soluble drugs, using a hydrophilic matrix system is
restricted due to rapid diffusion of the dissolved drug through the hydrophilic gel network.
Faster release of the drug from the hydrophilic matrix is probably due to faster dissolution of
the highly water-soluble drug from the core and its diffusion out of the matrix forming the
pores for entry of solvent molecules.
Hydrophobic controlled release agents are the most suitable controlled release agents for the
development of controlled release pharmaceutical compositions of Brivaracetam with high
water solubility. This is attributed to the decreased penetration of the solvent molecules in the
presence of a hydrophobic polymer leading to decreased diffusion of the drug from the
pharmaceutical composition.
Thus the present invention provides a controlled release pharmaceutical composition
comprising Brivaracetam or pharmaceutically acceptable derivative thereof and hydrophobic
release controlling agent.
Object of the invention
Therefore one embodiment provides controlled release pharmaceutical compositions
comprising Brivaracetam or pharmaceutically acceptable derivatives and hydrophobic release
controlling agent.
Further embodiment provides controlled-release pharmaceutical compositions comprising
Brivaracetam or pharmaceutically acceptable derivatives thereof and hydrophobic releasecontrolling
agent adapted to release Brivaracetam over a predetermined time period, at least
for about 24 hours. A suitable dissolution test is where the measurement is carried out in 900
ml of pH 6 phosphate buffer solution; using USP apparatus type II, at 50 rpm and at 37°C or
variations of this as well known to one who is skilled in the art.
Another embodiment proposes controlled release pharmaceutical compositions of
Brivaracetam or pharmaceutically acceptable derivatives thereof wherein the complete
dissolution time that is the time for release of at least 80% of the total amount of the drug is
between about 7 to about 24 hours, preferably between about 8 to about 20 hours when
dissolution is carried out in 900 ml of pH 6 phosphate buffer solution, using USP apparatus
type II. at 50 rpm and at 37°C or variations of this as well known to one who is skilled in the
art.
Further embodiment proposes controlled release pharmaceutical compositions of
Brivaracetam or pharmaceutically acceptable derivative thereof wherein pharmaceutical
composition releases at least about 40% of the drug in about 1.5 hours when dissolution is
carried out in 900 ml of pH 6 phosphate buffer solution, using USP apparatus type II, at 50
rpm and at 37°C or variations of this as well known to one who is skilled in the art.
Still further embodiment provides controlled release compositions comprising Brivaracetam
or pharmaceutically acceptable derivatives and hydrophobic release controlling agent for the
treatment of epilepsy and treatment of symptomatic myoclonus.
Brief description of the drawings
Fig l a shows a release profile of controlled release pharmaceutical composition of
Brivaracetam of Example 1, in 900 ml pH 6 phosphate buffer solution, USP apparatus Type
II, at 37° C, 50 rpm.
Fig lb shows a release profile of controlled release pharmaceutical composition of
Brivaracetam of Example 1, in 900 ml water, USP apparatus Type II, at 37° C, 50 rpm.
Fig 2 shows a release profile of controlled release pharmaceutical composition of
Brivaracetam of example 6, in 900 ml pH 6 phosphate buffer solution, USP apparatus Type
II, at 37° C. 50 rp .
Detailed description of the invention
One embodiment provides controlled release pharmaceutical compositions comprising
Brivaracetam or pharmaceutically acceptable derivatives thereof, which provides atleast
about 80% of the drug is released in 24 hrs or the pharmaceutical composition of the present
invention can be suitably designed to provide controlled release pharmaceutical compositions
that control release of the active over prolonged periods of time at least for. 20 hours after
oral administration.
As used herein "Brivaracetam ' also encompasses pharmaceutically acceptable derivatives of
Brivaracetam including enantiomers of Brivaracetam and mixture thereof, pharmaceutically
acceptable salts, esters, prodrugs, analogues and active metabolites of Brivaracetam and their
pharmaceutically acceptable salts, unless otherwise noted.
The amount of Brivaracetam or pharmaceutically acceptable derivatives may range from
about 2.5 to about 500 mg.
The term "controlled release pharmaceutical compositions" herein refers to any composition
or dosage form which comprises an active drug and which is formulated to provide a longer
duration of pharmacological response after administration of the dosage form than is
ordinarily experienced after administration of a corresponding immediate release
composition comprising the same drug in the same amount. Controlled release
pharmaceutical compositions include, inter alia, those compositions described elsewhere as
"extended release", "sustained release", "prolonged release", "programmed release", "time
release" and/or "rate controlled" compositions or dosage forms.
The controlled release pharmaceutical compositions are prepared using a pharmaceutically
acceptable "carrier" composed of materials that are considered safe and effective and may be
administered to an individual without causing undesirable biological side effects or unwanted
interactions. The "carrier" is all components present in the pharmaceutical formulation other
than the active ingredient or ingredients. The term "carrier" includes but is not limited to
diluents, binders, lubricants, glidants, dissolution enhancing agents and rate controlling
agents.
The rate-controlling agent(s) used in admixture with the active ingredient or in coating
comprises hydrophobic release controlling agents.
The hydrophobic release controlling agent(s) are selected from but are not limited to
polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose propionate (lower,
medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate,
cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl
methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl
methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl
methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly
(octadecyl acrylate), waxes such as beeswax, carnauba wax. paraffin wax, niicrocrystalline
wax, and. ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol
and myristyl alcohol, and fatty acid esters such as glyceryl monostearate; glycerol
monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl
palmitostearate, glyceryl behenate, or hydrogenated vegetable oils.
The controlled release pharmaceutical compositions comprise 2 to 70 % per weight of
hydrophobic release controlling agent with respect to the total weight of the composition,
preferably, 4 to 65 % per weight of hydrophobic release controlling agent; more preferably 5
to 50 % per weight of hydrophobic release controlling agent; and most preferably 6 to 40 %
per weight of hydrophobic release controlling agent with respect to the total weight of the
tablet.
Diluents may be, for example, any pharmaceutically acceptable, non-toxic diluents, for
example lactose, dextrose, sucrose, maltose, microcrystalline cellulose, starch, calcium
hydrogen phosphate, mannitol and the like.
Binders may be, for example, starch, sugars, gums, low molecular weight hydroxypropyl
methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or the like.
Lubricants may be, for example, talc, magnesium stearate, calcium stearate, stearic acid,
sodium stearyl fumarate, sodium benzoate or the like.
Glidants may be, for example, colloidal silicon dioxide, talc or the like.
The term "controlled release pharmaceutical compositions" includes a pharmaceutical
composition that encompasses one or more individual units. The individual units may be in
form of granules, pellets, minitablets or beads. Granules, pellets, minitablets or beads of the
present invention can be filled into a capsule or can be compressed into a tablet. The
compositions of the invention can be further coated with suitable nonfunctional or functional
coating.
The Examples below are representation only and should not be construed to limit the scope
of the invention:
Example 1:
Sr No Ingredients Mg/Tab
1 Brivaracetam 50.00
2 Lactose anhydrous 150.00
. Dibasic calcium phosphate anhydrous 33.50
4 Colloidal silicon dioxide 7.75
5 Hydrogenated vegetable oil 100.00
6 Talc 5.25
7 Magnesium Stearate 3.50
8 Core Tablet Weight 350
Seal Coating
9 Hydroxypropyl methylcellulose (HPMC E5) 7.778
10 Polyethylene glycol 0.778
11 Talc 0.778
12 Titanium dioxide 1.167
13 Isopropyl alcohol q.s
14 Methylene chloride q.s
15 Coated Tablet Weight 360.50
16 Opadry AMB 10.82
Final Tablet Weight 371 .32
Brief Manufacturing Procedure:
1) Sift Brivaracetam, Lactose anhydrous, Dibasic calcium phosphate a d Colloidal
silicon dioxide through #20 mesh and mix in a suitable mixer.
2) Melt hydrogenated vegetable oil (sterotex Type A) at 60 to 70°C until it melts
completely. Add the material of step 0 1 and granulate the same to get uniform
granules.
3) Cool the granules obtained from step 02 under room temp to congeal.
4) Pass the dried granules of step 03 through #20 mesh.
5) Blend the step 4 granules with Lactose, Dibasic calcium phosphate. Colloidal silicon
dioxide, talc and lubricate it with magnesium stearate and compress the lubricated
blend into tablets using suitable tooling.
6) Coat the step 5 tablets with seal coat and further coat with Opadry AMB coat to give
desired build up.
Example 2 :
Sr o Ingredients %w/w
1 Brivaracetam 5 - 17.5
2 ' Lactose anhydrous 20 - 60
Dibasic calcium phosphate
anhydrous 10 - 50
4 Colloidal silicon dioxide NF 0.5 - 5
5 Hydrogenated vegetable oil 10 - 60
6 Talc 0.5 5
7 Magnesium Stearate 0.5 - 3
8 Seal coat 1 - 3
9 AMB (Air Moisture Barrier) coat 1 - 3
Brief Manufacturing Procedure:
1) Sift Brivaracetam, Dibasic calcium phosphate, Lactose anhydrous and Colloidal
silicon dioxide through #20 mesh and mix in a suitable mixer.
2) Melt hydrogenated vegetable oil (sterotex Type A) at 60 to 70°C until it melts
completely. Add the material of step 1 and granulate the same to get uniform
granules.
3) Cool the granules obtained from step 2 under room temp to congeal.
4) Pass the dried granules of step 3 through #20 mesh.
5) Granulate step 4 blend with dibasic calcium phosphate, colloidal silicon dioxide, talc
and lubricate above blend with magnesium stearate and compress lubricated blend
into tablets using suitable tooling.
6) Coat above compressed tablets with HPMC (Hydroxypropyl methyl cellulose) E5,
PEG 6000. Talc and Titanium dioxide up to desired build up.
7) Coat above coated tablets with Opadry AMB white to give a 3% w/w build up.
Example-3:
S o Ingredients %w/w
1 Brivaracetam 5 - 17.5
2 Lactose anhydrous 25 - 65
Dibasic calcium phosphate
anhydrous 5 - 20
4 Colloidal silicon dioxide 0.5 - 5
5 Hydrogenated castor oil 10 - 60
6 Talc 0.5 - 5
7 Magnesium Stearate 0.5 - 3 .5
8 AMB coat 1 - 3
Brief Manufacturing Procedure:
) Sift Brivaracetam, Lactose anliydrous and Colloidal silicon dioxide through #20 mesh
and mix in a suitable mixer.
2) Melt Hydrogenated Castor Oil at 60 to 70°C until it melts completely. Add the
material of step 1 and granulate the same to get uniform granules.
3) Cool the granules obtained from step 02 under room temp to congeal.
4) Pass the dried granules of step 03 through #20 mesh.
5) Blend the granules of step 4 with Lactose, Dibasic calcium phosphate. Colloidal
silicon dioxide, talc and lubricate with magnesium stearate and compress lubricated
blend into tablets using suitable tooling.
6) Coat above coated tablets with Opadry AMB white to give a 3% w/w build up.
Example 4 :
S. No. Ingredients % w/w
Intra granular
1 Brivaracetam 15 - 25
2 Lactose monohydrate 30 - 70
Pre-gelatinised Starch 5- 25
Extra granular
4 Magnesium stearate 0.5 - 3
Ethyl cellulose - HPMC coating:
7 Ethyl cellulose 10 CPS 0.5 - 20
8 HPMC 15 cps 0.05 - 10
9 Dibutyl Sebacate 0.05- 4
10 Isopropyl alcohol q.s
11 Dichloro methane q.s
12 Opadry white AMB 1- 4
14 Purified water q.s
Brief Manufacturing Procedure:
1) Sift Brivaracetam, lactose and pregelatinised starch through # 30 ASTM mesh and
granulate water and dry the wet mass at 50°C - 55 °C.
2) Pass dried granules through # 25 ASTM mesh and lubricate with Magnesium stearate
(previously passed through # 40 mesh) for 5 min. and compress the tablets using
suitable punches.
3) Coated the above tablets with the solution of Ethyl cellulose and HPMC to a weight
gain of 0- 15 % w/w
4) Coat the step 3 tablets with Opadry white AMB to give a 3 % w/w build up.
Example 5 :
Brief Manufacturing Procedure:
1) Sift Brivaracetam, lactose and pregelatinised starch through # 30 ASTM mesh and
granulate water and dry the wet mass at 50°C - 55 °C.
2) Pass dried granules through # 30 ASTM mesh and lubricate with Magnesium stearate
(previously passed through # 40 mesh) for 5 minute and compress the tablets using
suitable punches into mini tablets.
3) Coat the above tablets with the solution of Ethyl cellulose and HPMC to a weight
gain of 10- 15 % w/w
4) Coat the step 3 tablets with Opadry white AMB to give a 3 % w/w build up.
5) Fill the coated tablets of step 4 into capsules of suitable size.
Example 6:
Brief Manufacturing Procedure:
1) Sift Brivaracetam, lactose and pregelatinised starch through # 30 ASTM mesh and
granulate water and dry the wet mass at 50°C - 55 °C.
2) Pass dried granules through # 25 ASTM mesh and lubricate with Magnesium stearate
(previously passed through # 40 mesh) for 5 min. and compress the tablets using
suitable punches.
3) Coat the above tablets with the solution of Ethyl cellulose and Povidone to a weight
gai of 10- 15 % w/w.
4) Coat the step 3 tablets with Opadry white AMB to give 3 % w/w build up.
Example 7:
Brief Manufacturing Procedure:
1) Sift Brivaracetam, Lactose anhydrous and Colloidal silicon dioxide through #20
mesh and mix in a suitable mixer.
2) Melt hydrogenated vegetable oil (sterotex Type A) at 60 to 70°C until it melts
completely. Add the material of step 0 1 and granulate the same to get uniform
granules.
3) Cool the granules obtained from step 02 under room temp to congeal.
4) Pass the dried granules of step 03 through #20 mesh.
5) Blend the step 4 granules with Lactose, Dibasic calcium phosphate, Colloidal silicon
dioxide, talc and lubricate it with magnesium stearate and compress the lubricated
blend into tablets using suitable tooling.
6) Fill the tablets of step 5 in a capsule of suitable size.
Example 8 :
Brief Manufacturing Procedure:
1) Dissolve Brivaracetam and HPMC in sufficient quantity of water and load this
solution on the sugar pellets using Fluidized Bed Processor.
2) Coat above drug loaded pellets using Ethyl cellulose and HPMC solution in (IPA:
DCM (1:1)) to give and required wt build up of 0- 25 %.
3) Fill the above-coated pellets into capsules or Blended with suitable compression -
aiding material and compressed into tablets.
CLAIMS
1. A controlled release pharmaceutical composition comprising Brivaracetam or
pharmaceutically acceptable derivative thereof and hydrophobic release controlling
agent.
2. The controlled release pharmaceutical composition according to claim 1, wherein the
hydrophobic release controlling agent is selected from ethyl cellulose, polyvinyl
acetate dispersion, cellulose acetate, cellulose propionate (lower, medium or higher
molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose
acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl
methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly
(hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate). poly
(phenyl methacrylate). poly (methyl acrylate). poly (isopropyl acrylate), poly
(isobutyl acrylate), poly (octadecyl acrylate), waxes such as beeswax, camauba wax,
paraffin wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl
alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol, and fatty acid esters such
as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides, tristearin,
tripalmitin, cetyl esters wax, glyceryl palmitostearate, hydrogenated vegetable oil or
glyceryl behenate.
3. The controlled release pharmaceutical composition according to claim 1, wherein the
hydrophobic release controlling agent is present in admixture with Brivaracetam or
pharmaceutically acceptable derivative thereof or in the coating.
4 . A controlled release pharmaceutical composition comprising a core and a coating
surrounding the core, wherein the core comprises Brivaracetam or pharmaceutically
acceptable derivative thereof and the coating comprises hydrophobic release
controlling agent.
5 . The controlled release pharmaceutical composition according to claim 4, wherein the
hydrophobic release controlling agent is selected from ethyl cellulose, polyvinyl
acetate dispersion, cellulose acetate, cellulose propionate (lower, medium or higher
molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose
acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl
methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly
(hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly
(phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly
(isobutyl acrylate) or poly (octadecyl acrylate).
6. The controlled release pharmaceutical composition according to claim 5, wherein the
hydrophobic release controlling agent is ethyl cellulose.
7. A controlled release pharmaceutical composition comprising Brivaracetam or
pharmaceutically acceptable derivatives thereof and hydrophobic release controlling
agent, wherein said composition has dissolution of Brivaracetam at least 80%
between about 7 to about 24 hours when measured in 900 ml of pH 6 phosphate
buffer solution using USP apparatus type II, at 50 rpm and at 37°C.
8. A controlled release pharmaceutical composition of claim 7, wherein the composition
has dissolution of Brivaracetam at least 80% between about 8 to about 20 hours when
measured in 900 ml of pH 6 phosphate buffer solution using USP apparatus type II, at
50 rpm and at 37°C.
9 . A controlled release pharmaceutical composition useful for the treatment of epilepsy
and treatment of symptomatic myoclonus comprises Brivaracetam or
pharmaceutically acceptable derivative thereof and hydrophobic release controlling
agent.