U.S. patent application number 12/944936 was filed with the patent office on 2011-03-17 for extended release formulation of levetiracetam.
This patent application is currently assigned to UCB Pharma S.A.. Invention is credited to Kaustubh Jinturkar, Rajesh Kshirsagar, Nilesh Malaviya, Ashwin Rao.
Application Number | 20110064808 12/944936 |
Document ID | / |
Family ID | 35788072 |
Filed Date | 2011-03-17 |
United States Patent
Application |
20110064808 |
Kind Code |
A1 |
Kshirsagar; Rajesh ; et
al. |
March 17, 2011 |
EXTENDED RELEASE FORMULATION OF LEVETIRACETAM
Abstract
The present invention relates to extended release pharmaceutical
compositions of Levetiracetam and processes for preparing the same.
The extended release tablet of Levetiracetam is with a core
comprising of Levetiracetam and water dispersible rate controlling
polymer, and the tablet core is optionally functional coated
comprising a combination of water non-dispersible and/or water
dispersible polymer. It provides extended therapeutically effective
plasma levels over a twenty four hour period with diminished
incidences of neuropsychiatric adverse events by eliminating the
troughs and peaks of drug concentration in a patient's blood
plasma. The composition also exhibits no food effect.
Inventors: |
Kshirsagar; Rajesh;
(Vadodara, IN) ; Rao; Ashwin; (Vadodara, IN)
; Malaviya; Nilesh; (Vadodara, IN) ; Jinturkar;
Kaustubh; (Vadodara, IN) |
Assignee: |
UCB Pharma S.A.
Brussels
BE
|
Family ID: |
35788072 |
Appl. No.: |
12/944936 |
Filed: |
November 12, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11583888 |
Oct 20, 2006 |
7863316 |
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12944936 |
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11215947 |
Aug 31, 2005 |
7858122 |
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11583888 |
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Current U.S.
Class: |
424/472 ;
514/424 |
Current CPC
Class: |
A61K 9/1635 20130101;
A61P 25/00 20180101; A61K 9/2054 20130101; A61K 31/4015 20130101;
A61P 25/08 20180101; A61K 9/2866 20130101; A61K 9/2077
20130101 |
Class at
Publication: |
424/472 ;
514/424 |
International
Class: |
A61K 9/28 20060101
A61K009/28; A61K 31/4015 20060101 A61K031/4015; A61K 9/36 20060101
A61K009/36; A61P 25/08 20060101 A61P025/08 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 27, 2005 |
IN |
81MUM2005 |
Claims
1. An extended release tablet of Levetiracetam comprising from
about 30% to about 85% w/w of the tablet of Levetiracetam and about
1% to about 50% w/w of the tablet of a water dispersible rate
controlling polymer, which exhibits no adverse food effect.
2. An extended release tablet formulation according to claim 1,
wherein said tablet exhibiting a value of
(AUC.sub.fed)/(AUC.sub.fasted) of at least 0.80 with a lower 90%
confidence limit of at least 0.75.
3. An extended release tablet formulation according to claim 1,
wherein said tablet is coated with a functional coat of about 1% to
15% w/w of the tablet weight comprising a combination of a water
non-dispersible polymer and a water dispersible polymer.
4. An extended release tablet formulation according to claim 1,
wherein when orally administered to a patient in need thereof
provides a peak plasma level of Levetiracetam in from about eight
to about sixteen hours and provides extended therapeutically
effective plasma levels over a twenty four hour period with
diminished incidences of neuropsychiatric adverse events by
eliminating the troughs and peaks of drug concentration in
vivo.
5. An extended release tablet according to claim 1, wherein the
tablet is comprised of from about 50% to 80% Levetiracetam w/w of
the tablet and about 20% to about 40% w/w of the tablet
hydroxypropyl methylcellulose.
6. An extended release tablet according to claim 5, wherein the
tablet further comprises about 1% to about 5% w/w of the tablet
povidone.
7. An extended release tablet according to claim 6, wherein the
tablet is coated with a functional coat comprising ethyl cellulose,
hydroxypropyl methylcellulose and polyethylene glycol.
8. An extended release tablet according to claim 1, wherein the
tablet is coated with a functional coat of about 1% to about 12%
w/w of the tablet weight, said functional coat comprising of from
about 70% to about 80% w/w of the functional coat of ethyl
cellulose, from about 20% to about 30% w/w of the functional coat
of hydroxypropyl methylcellulose and from 10 to about 20% w/w of
the functional coat of polyethylene glycol.
9. An extended release tablet according to claim 1 wherein the
tablet is coated with a functional coat of about 1% w/w to about
12% w/w of the tablet weight, said functional coat comprising of
from about 70% to about 80% w/w of the functional coat of ethyl
cellulose and from about 20% to about 30% w/w of the functional
coat of lactose.
10. An extended release tablet according to claim 1 having the
following dissolution profile in USP Apparatus 1 (basket) at 100
rpm in purified water at 37.degree. C.: TABLE-US-00018 Time (hours)
Average % Levetiracetam released 2 <35 4 35-75 12 >75
11. An extended release tablet according to claim 1, wherein the
tablet is comprised of from about 61% to 73% w/w of the tablet
levetiracetam and about 25% to about 35% w/w of the tablet.
hydroxypropyl methylcellulose
12. An extended release tablet according to claim 11, wherein the
tablet further comprises from about 1.1% to about 1.5% w/w of the
tablet povidone.
13. An extended release tablet according to claim 11, wherein the
tablet is coated with a functional coat of about 1.0% to about 6.0%
w/w of the tablet, said functional coat comprising of about 75% w/w
of the functional coat of ethyl cellulose and about 25% w/w of the
functional coat of hydroxypropyl methylcellulose.
14. An extended release tablet according to claim 11, wherein the
tablet is coated with a functional coat comprising of ethyl
cellulose, hydroxypropyl methylcellulose and polyethylene
glycol.
15. An extended release tablet according to claim 1, wherein said
tablet is coated with a functional coat of about 1-6% w/w of the
tablet.
16. An extended release tablet according to claim 15, wherein the
functional coat comprises of ethyl cellulose having a 44.0-51.0%
content of ethoxy groups and hydroxypropyl methylcellulose having
viscosity of 2-6 cps at 2% aqueous solution with a methoxy content
of 28.0-30.0% and a hydroxypropoxy group content of 7.0-12.0%.
17. An extended release tablet according to claim 1, wherein the
tablet is prepared by wet granulation, dry granulation or direct
compression.
18. An extended release tablet according to claim 1, wherein the
tablet is prepared by wet granulation, dry granulation or direct
compression and the core is coated either in a coating pan or in a
fluidized bed system.
19. The extended release tablet of claim 1 wherein the hydrophilic
polymer is in the form of Opadry ready mix.
Description
[0001] This application is a continuation-in-part (CIP) of U.S.
patent application Ser. No. 11/215,947, filed Aug. 31, 2005, which
is incorporated herein by reference.
FIELD OF INVENTION
[0002] This invention relates to an extended release pharmaceutical
composition of Levetiracetam with once a day dosage regime and the
process of preparing it.
BACKGROUND AND PRIOR ART
[0003] The use of high viscosity grade hydrophilic and the
hydrophobic polymers to produce extended or controlled release
pharmaceutical composition is known in the art. For extending the
release, the tablet comprising the drug also comprises of high
viscosity grade hydrophilic polymer. If required the tablets are
coated with hydrophobic polymer and pore forming agent. As soon as
the solid dosage form comes in contact with the surrounding media,
pores are formed and the drug is diffused through these pores. The
media enters the tablet core and results into the hydration of the
polymer which also controls the release of the drug. Control of the
rate of release benefits therapy by producing constant blood plasma
levels of the active ingredient and by decreasing the frequency of
administration, thereby improving the patient compliance to the
dosage regimen. The present invention provides a pharmaceutical
composition of extended release tablets of Levetiracetam suitable
for once daily administration to human subjects.
[0004] It is known that the absorption and bioavailability of any
particular therapeutic agent can be affected by numerous factors
when dosed orally. Such factors include the presence of food in the
gastrointestinal (GI) tract because, in general, the gastric
residence time of a drug is usually significantly longer in the
presence of food than in the fasted state. If the bioavailability
of a drug is affected beyond a certain point due to the presence of
food in the GI tract, the drug is said to exhibit a "food effect".
Food effects are important inasmuch as, when a drug exhibits an
adverse food effect, there is risk associated with administering it
to a patient who has eaten recently. The risk derives from the
potential that absorption into the bloodstream may be adversely
affected to the point that the patient risks insufficient
absorption to remediate the condition for which the drug was
administered.
[0005] Levetiracetam is chemically named as
(-)-(S)-.alpha.-ethyl-2-oxo-1-pyrrolidine acetamide with molecular
formula C.sub.8H.sub.14N.sub.2O.sub.2 and molecular weight 170.21.
Levetiracetam is white to off white crystalline powder and has
aqueous solubility of 104 gm/ml. It is freely soluble in chloroform
(65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol
(16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL)
and practically insoluble in n-hexane. Levetiracetam is described
in the U.S. Pat. Nos. 4,837,223, 4,943,639 and 6,107,492.
[0006] Levetiracetam is indicated as adjunctive therapy in the
treatment of partial onset seizures in adults with epilepsy. The
precise mechanism(s) by which Levetiracetam exerts its
antiepileptic effect is unknown and does not appear to derive from
any interaction with known mechanisms involved in inhibitory and
excitatory neurotransmission. Levetiracetam is rapidly absorbed
with the oral bioavailability of 100%. Food does not affect the
extent of absorption of Levetiracetam but it decreases Cmax by 20%
and delays Tmax by 1.5 hours. The pharmacokinetics of Levetiracetam
are linear over a dose range of 500-5000 mg, with steady state
kinetics being achieved 2 days after multiple twice daily dosing.
It is less than 10% bound to plasma proteins. Levetiracetam has
plasma elimination half life of 7.+-.1 hr with the volume of
distribution of 0.6 L/Kg. The total body clearance is 0.9 ml/min/kg
and the renal clearance is 0.6 ml/min/kg. Its elimination is
correlated with creatinine clearance. There is no age, gender, race
or circadian effect.
[0007] Presently Levetiracetam is administered to adults as
conventional immediate release tablets. The current dosing regimen
includes twice daily administration. Levetiracetam is available as
an immediate release and is approved for sale in various countries
including the United States of America under the brand name
KEPPRA.TM. (UCB Pharma.). KEPPRA.TM. is available in 250, 500 and
750 mg strengths as the immediate release tablet formulation.
[0008] In the Biopharmaceutics Classification System, it belongs to
Class I since it is highly soluble (1.04 g/ml), highly permeable
(F>90%) and >85% of the tablet amount released in 15 minutes
in three different pH media. Clinically, it does not belong to
narrow therapeutic class because it has a relatively low order of
toxicity and a relatively high therapeutic index.
[0009] The twice daily dosing regimen for immediate-release
Levetiracetam tablets is well tolerated with few incidences of
neuropsychiatric adverse events like, somnolence, fatigue,
coordination difficulties and behavioral abnormalities. The adverse
effects are proportionate to the drug plasma level and therefore
for improving the therapeutic efficacy, reducing incidences of
adverse events and enhancing patient compliance an extended release
once-daily regimen is explored in the present invention.
[0010] WO 01/51033 provides for a Solid pharmaceutical compound
that can be administered orally, permitting controlled release of
at least one active substance which can be Levetiracetam consisting
of a homogeneous mixture comprising active substance, at least one
matrix excipient between 5 and 95% by weight in relation to total
weight of the compound, selected among the inert matrices, the
hydrophilic, or lipid matrices, mixtures of inert and lipidic
matrices mixture of hydrophilic and inert matrices; at least one
entero-soluble polymer between 2 and 50% by weight in relation to
the total weight of the compound and at least one alkalinizing
agent soluble in a aqueous phase under conditions of physiological
pH, of at least 0.5 to 50% by weight in relation to the total
weight of the compound.
[0011] WO 03/101428 provides for a method for the manufacture of a
pharmaceutical compound with retarded release of the active
principle, which can be Levetiracetam. A mixture of active
substance and the polymer that provides the retarded release are
compressed by putting them through two rollers that have a
temperature of more than 40.degree. C. and compaction force is
exerted on it of more than 15 to 40 kN/cm roller width. The
compressed mixture is powdered to the desired particle size and if
required the process is repeated.
OBJECTIVES OF INVENTION
[0012] The object of the present invention is to provide an
extended release pharmaceutical composition of Levetiracetam, which
upon ingestion results in blood plasma levels having plateau
effect, for an extended period of time
[0013] Another object of the present invention is to produce a
pharmaceutical composition which releases Levetiracetam in
predetermined manner.
[0014] Yet another object of the present invention is to provide
extended release pharmaceutical composition of Levetiracetam for
once daily dosage regimen.
[0015] Yet another object of the present invention is to provide a
extended release composition of Levetiracetam which does not
exhibit food effect.
[0016] Yet another object of the present invention is to provide an
extended release composition of Levetiracetam which shows reduced
inter subject variability.
SUMMARY OF THE INVENTION
[0017] The present invention relates to compositions of and
processes of preparing an extended release pharmaceutical
composition of Levetiracetam which comprises Levetiracetam,
optionally a binder, hydrophilic rate controlling polymer and
conventional pharmaceutically acceptable excipients, the blend is
compressed into a tablet and the formed tablet is further coated
with a functional coating comprising of a hydrophobic rate
controlling polymer. The functional coating optionally comprises of
a channeling agent which can be a hydrophilic polymer or a water
soluble substance. The composition may be further coated with a
polymer based non functional coating. The components are selected
in such a way to give extended release of Levetiracetam in a
predetermined manner.
[0018] Preferably, the present invention relates to the extended
release formulation which comprises from about 30% w/w to about 85%
w/w of Levetiracetam, from about 1% w/w to about 50% w/w of
hydrophilic polymer and optionally from about 1% w/w to about 10%
w/w binder. All these weights are in relation to the weight of the
core tablets. The tablet is further functional coated with a
hydrophobic polymer, which comprises of about 2% w/w to about 15%
w/w of the weight of core tablet. The coating optionally comprises
channeling agent from about 10% w/w to about 60% w/w of the total
weight of the coating layer. Further the coated tablet is given a
nonfunctional coating which comprises about 1% w/w to 3% w/w of the
total weight of the composition.
[0019] More preferably the present invention relates to the
extended release formulation which comprises from about 50% w/w to
about 75% w/w of Levetiracetam, from about 0.5% to about 5%
Polyvinyl pyrrolidone, from about 20% w/w to about 45% w/w
Hydroxypropyl Methylcellulose. The functional coating on the
tablets comprises of from about 2% w/w to about 5% w/w of the total
weight of the composition. The coating comprises from about 50% w/w
to about 80% w/w ethyl cellulose as functional polymer and from
about 15% w/w to about 35% w/w Hydroxypropyl Methylcellulose, as a
channeling agent.
[0020] According to the present invention, the extended release
formulation is prepared by compression of a matrix tablet followed
by functional coating, the said method comprising steps of: [0021]
i. Blending Levetiracetam or its granules prepared by dry or wet
granulation with the rate controlling polymer. [0022] ii.
Lubricating the blended mixture and compressing into tablets of
appropriate shape. [0023] iii. Coating the tablets with an aqueous
dispersion of water insoluble and water soluble polymer. [0024] iv.
Coating the tablets with an aqueous dispersion of the nonfunctional
coating polymer.
BRIEF DESCRIPTION OF DRAWINGS
[0025] FIG. 1 is a plot showing the drug release profile of
Levetiracetam from four different compositions of the drug in
matrices using USP I, 100 rpm and at 37.degree. C.
[0026] FIG. 2 is a plot showing the comparative plasma level
profile of Levetiracetam under Fed dosing in Healthy Human
volunteers.
DETAILED DESCRIPTION OF THE INVENTION
[0027] In an embodiment of the present invention, the extended
release tablet comprises of active ingredient and water soluble
rate controlling polymer and optionally conventional excipients
including a binder. These tablets are coated with a combination of
water insoluble polymer. The coating optionally includes a water
soluble polymer or substance as a channeling agent. The functional
coated tablets are further coated with water soluble polymer as non
functional coat.
[0028] According to the embodiment of the present invention the
active ingredient is used as such, inclusive or exclusive of the
binder, if the crystal morphology is favoring direct compression.
However, if the particles are not favoring direct compression and
granulation is required then it is carried out either as `dry
granulation` or as `wet granulation`. The dry granulation process
involves the mixing of drug with the binder or directly with the
rate controlling hydrophilic polymer or both, followed by slug
formation on tablet press or using the roll compactors. The process
of wet granulation includes aqueous or non aqueous granulation. The
wet granulation process comprises the admixing of the active
ingredient with `diluent` or mixture of `diluent` and rate
controlling hydrophilic polymer, and granulation of the blend with
the binder mass to form the wet mass followed by drying and sizing.
The binder may optionally be admixed with the dry blend and
granulation performed with aqueous or non aqueous solvent. The
solvent for the non aqueous granulation is selected from ethanol,
isopropyl alcohol and dichloromethane.
[0029] According to the present invention, the pharmaceutical
composition contains Levetiracetam as an active ingredient. The
Levetiracetam may be present in an amount from about 40% to about
80%, more preferably form about 50% to about 75% by weight of
extended release composition.
[0030] In the preferred embodiment of the present invention
Levetiracetam is granulated using aqueous granulation with a binder
solution. The binder used is essentially important to impart
compressibility, flow property and strength/hardness. The binder
can be selected from Polyvinyl pyrrolidone, Hydroxypropyl
cellulose, Hydroxypropyl Methylcellulose (low viscosity grade),
methyl cellulose, starch, pregelatinized starch, modified corn
starch, polyacryl amide, poly-N-vinyl amide, sodium carboxymethyl
cellulose, polyethylene glycol, gelatin, polyethylene oxide, poly
propylene glycol, tragacanth, alginic acid, combinations there of
and other materials known to one of ordinary skill in the art. The
binder may be present in an amount from about 0.01% to about 10%,
preferably from about 0.5% to about 5% by weight of the extended
release composition.
[0031] According to the embodiment of the present invention the
active granules are blended with hydrophilic rate controlling
polymer of high viscosity grade as a part of the matrix system. The
high viscosity grade is the one which provide viscosity greater
than 15 cps in a 2% w/w solution. The hydrophilic rate controlling
polymer in the matrix system includes Hydroxyethyl cellulose,
Hydroxypropyl cellulose, sodium alginate, carbomer (Carbopol.TM.),
sodium carboxymethyl cellulose, xanthan gum, guar gum, locust bean
gum, poly vinyl acetate, polyvinyl alcohol and Hydroxypropyl
Methylcellulose (high viscosity grade). The matrix forming polymer
comprises from about 1% to about 50%, preferably from about 20% to
about 40% by weight of the coated extended release composition.
[0032] In yet another embodiment the present invention discloses an
extended release pharmaceutical composition of levetiracetam which
does not exhibit a food effect. The present invention provides an
extended release compositions of Levetiracetam which can be
administered to a mammal (including humans) in fed state and which
exhibits a mean (AUC.sub.fasting)/(AUC.sub.fed) of at least 0.80.
In particular, the present invention provides an extended release
compositions of Levetiracetam which can be administered to a mammal
(including humans) in fed state and which exhibits a mean
(AUC.sub.fasting)/(AUC.sub.fed) of at least 0.80 and/or with a
lower 90% confidence limit of at least 0.75.
[0033] According to the embodiment of the present invention, for
definitional purposes, and specifically with respect to
Levetiracetam extended release compositions only, a dosage form of
Levetiracetam exhibits a food effect if, after dosing a population,
once fasted and once fed, the mean (AUC.sub.fasting)/(AUC.sub.fed)
is below the value 0.80 and/or the lower 90% confidence limit for
this ratio is below 0.75. Conversely, a dosage form of
Levetiracetam which does not exhibit a food effect is one which,
when tested on a test population, exhibits a value for
(AUC.sub.fasting)/(AUC.sub.fed) of at least 0.80 and/or a lower 90%
confidence limit for this value is at least 0.75. The value for
mean (AUC.sub.fasting)/(AUC.sub.fed) can be any value above 0.80
and still be within the scope of this invention, though it is
preferred that it can have an upper (mean) limit of 1.25, and/or an
upper 90% confidence limit of 1.40 or below.
[0034] In addition to the above ingredients the extended release
tablets as described here also contains the lubricant, anti
adherent and a glidant. Antiadherents include, by way of example
and without limitation, magnesium stearate, talc, calcium stearate,
glyceryl behenate, Polyethylene glycols, hydrogenated vegetable
oil, mineral oil, stearic acid and other materials known to one of
ordinary skill in the art. Glidants include cornstarch, talc,
calcium silicate, magnesium silicate, colloidal silicon dioxide,
silicon hydrogel and other materials known to one of ordinary skill
in the art. Lubricants include, by way of example and without
limitation, calcium stearate, magnesium stearate, sodium stearyl
fumerate, glyceryl palmitostearate, glyceryl stearate, mineral oil,
stearic acid, and zinc stearate and other materials known to one of
ordinary skill in the art. The glidants, lubricants and anti
adherents are individually present in the range from about 0.01% to
about 5% w/w of the coated tablets. Preferably the glidants, anti
adherents and lubricants are present in the range from about 0.5%
to about 4% weight of the coated tablets, either alone or in
combination.
[0035] The formed extended release tablets are coated with a
hydrophobic rate controlling polymeric coat and the rate
controlling polymeric coat is composed of hydrophobic polymer,
hydrophobic or hydrophilic plasticizer and/hydrophilic pore forming
polymer (channeling agent). The hydrophobic film forming polymer is
selected from the group consisting of cellulose ether such as ethyl
cellulose, cellulose acetate, polyvinyl acetate, methacrylic acid
esters neutral polymer, polyvinyl alcohol-maleic anhydride
copolymers and the like. Even the commercially available dispersion
of film formers namely, Eudragit L-30D, Eudragit NE 30D, Aquacoat
ECD-30, Surelease E-7, Eudragit RS 30D, Eudragit RL 30D, etc. may
be used for the purpose of providing rate controlling coat. The
hydrophilic pore forming polymer in the rate controlling coat is
said to be selected from copolyvidone, Polyvinyl pyrrolidone,
polyethylene glycols, Hydroxyethyl cellulose, Hydroxypropyl
Methylcellulose (low viscosity grade). In the current embodiment,
the water insoluble polymer is present in an amount from 40% to
about 90%, preferably from about 50% to about 80% by weight of the
functional coating layer of extended release composition. The water
soluble pore forming polymer is present in an amount from about 10%
to about 60%, preferably from about 15% to about 35% by weight of
the coating layer. Additionally the coating dispersion may also
comprise of plasticizer to modify the properties and
characteristics of the polymers used on the coat of the compressed
tablets. Plasticizers useful in the invention can include, by way
of example and without limitation, low molecular weight polymers,
oligomers, copolymers, oils, small organic molecules, low molecular
weight polyols having aliphatic hydroxyls, ester-type plasticizers,
glycol ethers, poly(propylene glycol), multi-block polymers, single
block polymers, low molecular weight poly(ethylene glycol), citrate
ester-type plasticizers, triacetin, propylene glycol and glycerin.
Such plasticizers can also include ethylene glycol, 1,2-butylene
glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol,
triethylene glycol, tetraethylene glycol and other poly(ethylene
glycol) compounds, monopropylene glycol monoisopropyl ether,
propylene glycol monoethyl ether, ethylene glycol monoethyl ether,
diethylene glycol monoethyl, ether, sorbitol lactate, ethyl
lactate, butyl lactate, ethyl glycolate, dibutylsebacate,
acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,
tributyl citrate and allyl glycolate. Also the combination of the
plasticizers can be used in the present formulation. The
composition in the present embodiment preferably comprises 1.0 to
10.0% of hydrophobic polymer per weight of the coated tablets;
optionally up to 5% per weight of hydrophilic pore forming polymer
of the coated tablets and optionally up to 2% of plasticizer per
weight of the coated tablets.
[0036] According to the present invention, the non-functional
coating is selected from the group of ready to form dispersion such
as OPADRY. The OPADRY comprises of the hydrophilic (low viscosity
grade) film forming polymer, suitable colorant and the opacifying
agent. Opacifying agent include by titanium dioxide and other
materials known to one of ordinary skill in the art. Colorant
include, by way of example and without limitation, FD&C Red No.
3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2,
D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8,
caramel, and ferric oxide, red, other F.D. & C. dyes and
natural coloring agents such as grape skin extract, beet red
powder, beta-carotene, annato, carmine, turmeric, paprika, and
other materials known to one of ordinary skill in the art.
[0037] It should be understood, that compounds used in the art of
pharmaceutical formulation generally serve a variety of functions
or purposes. Thus, if a compound named herein is mentioned only
once or is used to define more than one term herein, its purpose or
function should not be construed as being limited solely to that
named purpose(s) or function(s).
[0038] Without further description, it is believed that one of
ordinary skill in the art can, using the preceding description and
the following illustrative examples, make and utilize the compounds
of the present invention and practice the claimed methods. The
following examples are given to illustrate the present invention.
It should be understood that the invention is not to be limited to
the specific conditions or details described in these examples
Examples 1-2
TABLE-US-00001 [0039] TABLE 1 Composition Sr. Weight in mgs No.
Ingredient Ex. 1 Ex. 2 1 Levetiracetam 500.00 500.00 2 Povidone
05.00 05.00 3 Purified water q.s. q.s. 4 Hydroxypropyl
Methylcellulose (HV) 300.00 300.00 5 Magnesium Stearate 10.00 10.00
6 Colloidal silicon dioxide 5.00 5.00 7 Aqueous dispersion of Ethyl
cellulose -- 24.30 (solid content) Total 820 844.30 q.s. means
quantity sufficient.
[0040] Levetiracetam 500 mg was sifted through s. s. sieve of mesh
40 and was then granulated with aqueous Polyvinyl pyrrolidone
solution and the granulated mass was dried at 50.degree. C. The
dried granules were sized through s. s. sieve of 20 mesh and these
granules were blended with Hydroxypropyl Methylcellulose,
lubricated with magnesium stearate and colloidal silicon dioxide
and the lubricated granules were compressed into tablets.
[0041] As mentioned in Table 1 the tablets of example 2 were
further coated with aqueous dispersion of hydrophobic rate
controlling ethyl cellulose to weight gain of 2.96% w/w of the
compressed tablet. Following the functional coating the tablets
were cured at 55.degree. C. for 1 hour.
Example 3
TABLE-US-00002 [0042] TABLE 2 Composition Sr. Weight in mgs No.
Ingredient Ex. 3 1 Levetiracetam 500.00 2 Povidone 05.00 3 Purified
water q.s. 4 Hydroxypropyl Methylcellulose (HV) 300.00 5 Magnesium
Stearate 10.00 6 Colloidal silicon dioxide 5.00 7 Aqueous
dispersion of Ethyl cellulose 35.82 (solid content) 8 Opadry 42.98
Total 898.80 q.s. means quantity sufficient.
[0043] Levetiracetam 500 mg was sifted through s. s. sieve of mesh
40 and was then granulated with aqueous Polyvinyl pyrrolidone
solution and the granulated mass was dried at 50.degree. C. The
dried granules were sized through s. s. sieve 20 mesh and these
granules were blended with Hydroxypropyl Methylcellulose,
lubricated with magnesium stearate and colloidal silicon dioxide
and lubricated granules were compressed into tablets. The
compressed tablets were coated with the mixture of aqueous
dispersion of ethyl cellulose and Opadry to a weight gain of 9.60%
w/w of the compressed tablets. Following the functional coating the
tablets were cured at 55.degree. C. for 1 hour.
Example 4
TABLE-US-00003 [0044] TABLE 3 Composition Sr. Weight in mgs No.
Ingredient Ex. 4 1 Levetiracetam 500.00 2 Povidone 10.00 3 Purified
water q.s. 4 Hydroxypropyl Methylcellulose (HV) 285.00 5 Magnesium
Stearate 10.00 6 Colloidal silicon dioxide 5.00 7 Opadry 16.30 8
Talc 5.00 Total 831.30 q.s. means quantity sufficient.
[0045] Levetiracetam 500 mg was sifted through s. s. sieve of mesh
40 and was then granulated with aqueous Polyvinyl pyrrolidone
solution and the granulated mass was dried at 50.degree. The dried
granules were sized through s. s. sieve of 20 mesh and these
granules were blended with Hydroxypropyl Methylcellulose,
lubricated with magnesium stearate, talc and colloidal silicon
dioxide and lubricated granules were compressed into tablets. The
compressed tablets were coated with Opadry to a weight gain of 2%
w/w of the compressed tablets.
Examples 5-6
TABLE-US-00004 [0046] TABLE 4 Composition Sr. Weight in mgs No.
Ingredient Ex. 5 Ex. 6 1 Levetiracetam 500.00 500.00 2 Povidone
10.00 10.00 3 Purified water q.s. q.s. 4 Hydroxypropyl
Methylcellulose (HV) 285.00 285.00 5 Magnesium Stearate 10.00 10.00
6 Colloidal silicon dioxide 5.00 5.00 7 Aqueous dispersion of Ethyl
cellulose 15.28 30.56 (solid content) 8 Opadry 16.71 17.12 9 Talc
5.00 5.00 10 Hydroxypropyl Methylcellulose (LV) 5.10 10.19 Total
852.09 872.87 q.s. means quantity sufficient.
[0047] Levetiracetam 500 mg was sifted through s.s. sieve of mesh
40 and was then granulated with aqueous Polyvinyl pyrrolidone
solution and the granulated mass was dried at 50.degree. C. The
dried granules were sized through s. s. sieve of 20 mesh and these
granules were blended with Hydroxypropyl Methylcellulose,
lubricated with magnesium stearate, talc and colloidal silicon
dioxide and the lubricated granules were compressed into
tablets.
[0048] The tablets of example 5 and 6, as mentioned in the table 4,
were coated with mixture of aqueous dispersion of ethyl cellulose
and Hydroxypropyl Methylcellulose (LV; low viscosity) in the ratio
of 75:25 (solid content). The tablets were coated to target weight
gain of 2.5% w/w and 5.0% w/w of the compressed tablets for example
5 and example 6 respectively. Following the coating the tablet were
cured at 65.degree. C. for 1 hr.
[0049] The coated tablets were further coated with Opadry to a
weight gain of 2% w/w of the functional coated tablet.
Example 7
[0050] The extended release tablets of Examples 1 to Example 6 were
tested for dissolution of Levetiracetam using 900 ml of pH 6.8
phosphate buffer as dissolution media at 37.degree. C. and in
40-mesh basket (USP Type 1) at 100 rpm
[0051] The dissolution profiles are recorded in Table 5.
TABLE-US-00005 TABLE 5 Dissolution Profile Percentage Levetiracetam
dissolved Time (hrs) Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 1 26 0 16
30 16 10 2 40 3 30 43 30 23 3 51 7 41 53 41 34 4 60 14 51 61 51 43
6 75 27 67 74 66 58 8 88 41 81 83 80 69 10 98 54 94 90 90 78 12 105
66 103 94 99 85
Example 8
TABLE-US-00006 [0052] TABLE 6 Composition Sr. Weight in mgs No.
Ingredient Ex. 8 1 Levetiracetam 750.00 2 Povidone 15.00 3 Purified
water q.s. 4 Hydroxypropyl Methylcellulose (HV) 316.00 5 Magnesium
Stearate 12.00 6 Colloidal silicon dioxide 6.00 7 Talc 6.00 8
Aqueous dispersion of Ethyl cellulose 16.58 (solid content) 9
Opadry 22.54 10 Hydroxypropyl Methylcellulose (LV) 5.52 Total
1149.64 q.s. means quantity sufficient.
[0053] Levetiracetam 750 mg was sifted through s. s. sieve of mesh
40 and was then granulated with aqueous Polyvinyl pyrrolidone
solution and the granulated mass was dried at 50.degree. C. The
dried granules are sized through s. s. sieve of 20 mesh and these
granules were blended with Hydroxypropyl Methylcellulose and then
lubricated with magnesium stearate, colloidal silicon dioxide and
talc and the lubricated granules were compressed into tablets.
[0054] The tablets as mentioned in the table 6, were coated with
mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl
Methylcellulose LV in the ratio of 75:25 (solid content). The
tablets were coated to target weight gain of 2.0% w/w. Following
the coating the tablet were cured at 65.degree. C. for 1 hr.
[0055] The coated tablets were further coated with Opadry to a
weight gain of 2% w/w of the functional coated tablet.
Example 9
TABLE-US-00007 [0056] TABLE 7 Composition Sr. Weight in mgs No.
Ingredient Ex. 9 1 Levetiracetam 750.00 2 Carbopol (71 G) 330 3
Glyceryl Behenate 15 4 Colloidal silicon dioxide 5 5 Talc 5 Total
1105 q.s. means quantity sufficient.
[0057] Levetiracetam 750 mg and carbopol were sifted through s. s.
sieve of mesh 30 and were blended together. The blend was
lubricated with glyceryl behenate, colloidal silicon dioxide and
talc and the lubricated blend was compressed into tablets.
Example 10
TABLE-US-00008 [0058] TABLE 8 Composition Sr. Weight in mgs No.
Ingredient Ex. 10 1 Levetiracetam 750.00 2 Polyvinyl Acetate 275 3
Glyceryl Behenate 15 4 Colloidal silicon dioxide 5 5 Talc 5 6
Aqueous dispersion of Ethyl cellulose 15.00 (solid content) 7
Opadry 20 8 Hydroxypropyl Methylcellulose (LV) 5 Total 1145 q.s.
means quantity sufficient.
[0059] Levetiracetam 750 mg and Kollidon SR (Polyvinyl Acetate:
Polyvinyl Pyrolidone, 8:2) were sifted through s. s sieve of mesh
30 and blended together. The blend was lubricated with glyceryl
behenate, colloidal silicon dioxide and talc and the lubricated
blend was compressed into tablets.
[0060] The tablets as mentioned in the table 8, were coated with
mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl
Methylcellulose (LV) in the ratio of 75:25 (solid content). The
tablets were coated to target weight gain of 1.90% w/w of the
uncoated tablets. Following coating the tablet were cured at
65.degree. C. for 1 hr.
[0061] The functional coated tablets were further coated with
Opadry to a weight gain of 1.87% w/w of the functional coated
tablet.
Example 11
TABLE-US-00009 [0062] TABLE 9 Composition Sr. Weight in mgs No.
Ingredient Ex. 11 1 Levetiracetam 750.00 2 Hydroxypropyl
Methylcellulose (HV) 350 3 Magnesium stearate 12.00 4 Colloidal
silicon dioxide 6.00 5 Talc 6.00 6 Aqueous dispersion of Ethyl
cellulose 15.00 (solid content) 7 Opadry 20 8 Hydroxypropyl
Methylcellulose (LV) 5 Total 1164 q.s. means quantity
sufficient.
[0063] Levetiracetam 750 mg and hydroxyl propyl methyl cellulose
(HV) were sifted through s. s. sieve of mesh 40 and blended
together. The blend was compacted using a roll compactor
(Chilsonator) to form slugs. The slugs were sized in an oscillating
granulator using a s. s. sieve of mesh 20. Obtained granules were
lubricated with magnesium stearate, colloidal silicon dioxide and
talc. The lubricated blend was compressed into tablets.
[0064] The tablets as mentioned in the table 9 were coated with
mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl
Methylcellulose (LV) in the ratio of 75:25 (solid content). The
tablets were coated to target weight gain of 1.78% w/w of the
uncoated tablets. Following the coating the tablet were cured at
65.degree. C. for 1 hr.
[0065] The functional coated tablets were further coated with
Opadry to a weight gain of 1.75% w/w of the functional coated
tablet.
Example 12
TABLE-US-00010 [0066] TABLE 10 Composition Sr. Weight in mgs No.
Ingredient Ex. 12 1 Levetiracetam 750.00 2 Hydroxypropyl
Methylcellulose (HV) 271 3 Hydroxypropyl cellulose 45.00 4
Magnesium stearate 12.00 5 Colloidal silicon dioxide 6.00 6 Talc
6.00 7 Aqueous dispersion of Ethyl cellulose 15.00 (solid content)
8 Opadry 20 9 Hydroxypropyl Methylcellulose (LV) 5 Total 1164 q.s.
means quantity sufficient
[0067] Levetiracetam 750 mg and Hydroxylpropyl Methylcellulose (HV)
were sifted through s. s. sieve of mesh 40 and blended together.
The blend was granulated using nonaqueous granulation using
Hydroxypropyl Cellulose as the binder. The granulated mass was
dried at 45.degree. C. The dried granules were sized through s. s.
sieve of mesh 20 and the granules were lubricated with Magnesium
Stearate, Talc and Colloidal Silicon dioxide. The lubricated blend
was compressed into tablets.
[0068] The tablets as mentioned in the table 10 were coated with
mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl
Methylcellulose LV in the ratio of 75:25 (solid content). The
tablets were coated to target weight gain of 1.78% w/w of the
uncoated tablets. Following the coating the tablet were cured at
65.degree. C. for 1 hr.
[0069] The coated tablets were further coated with Opadry to a
weight gain of 1.75% w/w of the functional coated tablet.
Example 13
TABLE-US-00011 [0070] TABLE 11 Composition Sr. Weight in mgs No.
Ingredient Ex. 13 1 Levetiracetam 750.00 2 Hydroxypropyl cellulose
45.00 3 Hydroxyethyl cellulose (HV) 271 4 Magnesium stearate 12.00
5 Colloidal silicon dioxide 6.00 6 Talc 6.00 7 Aqueous dispersion
of Ethyl cellulose 15.00 (solid content) 8 Opadry 20 9
Hydroxypropyl Methylcellulose (LV) 5 Total 1164 q.s. means quantity
sufficient.
[0071] Levetiracetam 750 mg was sifted through s. s. sieve of mesh
40 and was then granulated with non aqueous Hydroxypropyl cellulose
solution and the granulated mass was dried at 45.degree. C. The
dried granules are sized through s. s. sieve of mesh 20 and these
granules were blended with Hydroxyethyl cellulose and lubricated
with magnesium stearate, colloidal silicon dioxide and talc. The
lubricated granules were compressed into tablets.
[0072] The tablets as mentioned in the table 11, were coated with
mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl
Methylcellulose (LV) in the ratio of 75:25 (solid content). The
tablets were coated to target weight gain of 1.78% w/w. The coated
tablet were cured at 65.degree. C. for 1 hr.
[0073] The functional coated tablets were further coated with
Opadry to a weight gain of 1.75% w/w of the functional coated
tablet.
Example 14
[0074] The extended release tablets of Examples 8 to Example 13
were tested for dissolution of Levetiracetam using 900 ml of pH 6.8
phosphate buffer as dissolution media at 37.degree. C. and in
40-mesh basket (USP Type 1) at 100 rpm
[0075] The dissolution profiles are recorded in Table 12.
TABLE-US-00012 TABLE 12 Dissolution Profile Percentage
Levetiracetam dissolved Time (hrs) Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12
Ex. 13 1 17 23 9 18 6 6 2 30 44 26 33 12 30 3 41 59 45 45 22 48 4
49 72 59 55 31 60 6 63 91 78 72 49 82 8 76 101 93 85 66 94 10 85 99
98 95 79 99 12 91 98 97 101 91 97
Example 15
[0076] An in vivo study was conducted in healthy human volunteers
to assess bioavailability of Levetiracetam formulated as the
extended release tablets of Example 8 by comparison with a
reference treatment with immediate release Levetiracetam
tablets.
Method
[0077] The study followed an open label, two-treatment,
two-periods, comparative oral bioavailability study in healthy,
adult, male, human subjects under fed conditions. The subjects
received each of the two treatments during the course of the study,
which was conducted at a single center. The subjects were given
1500 mg oral dose of Levetiracetam. In the case of the IR
formulation, which was provided as Keppra.RTM. tablets, two equally
divided doses of 750 mg each were given at 12 hour interval
beginning in the morning. In the case of the extended release
formulation of Example 8, two tablets of 750 mg were given at a
time in the morning. Plasma Levetiracetam concentrations were
quantified by HPLC method. Samples were not diluted prior to
analysis as all sample concentrations were within the limits of
quantitation. Pharmacokinetic parameters for Levetiracetam were
estimated by non compartmental methods. The parameters Tmax, Cmax,
AUC.sub.0.fwdarw.t, AUC.sub.0.fwdarw..infin. were estimated during
the studies and recorded in Table 13.
Results
[0078] Mean plasma Levetiracetam concentrations over the 36 hour
assessment period are shown in FIG. 2.
TABLE-US-00013 TABLE 13 Formulation of Keppra Parameter Unit
Example 8 tablets 750 mg Cmax .mu.g/ml 17.194 .+-. 4.23 22.23 .+-.
5.44 Tmax Hrs 12-13 2-3 and 14-15 AUC (0.fwdarw.t) ug h/mL 345.81
.+-. 105.45 375.267 .+-. 76.86 AUC (0.fwdarw.inf) .mu.g h/mL
383.855 .+-. 125.87 413.854 .+-. 91.50
Example 16-18
TABLE-US-00014 [0079] TABLE 14 Composition Sr. Weight in mgs No
Ingredient Ex. 16 Ex. 17 Ex. 18 1 Levetiracetam 750.00 500.00 1000
2 Povidone USP 10.00 10.00 20 (Plasdone K 90 D) 3 Purified water
q.s. q.s. q.s. 4 Hypromellose 2208 (Methocel 250.00 167.00 333
K100M CR) USP 5 Hypromellose 2208 (Methocel 41.00 27.00 55 K100 LV)
USP 6 Colloidal silicon dioxide 6 4 8 7 Magnesium Stearate NF 12 8
16 8 Talc BP 6 4 8 9 Ethyl cellulose 7 cps 19.65 13.10 26.20 10
Polyethyleneglycol 4000 7.56 5.04 10.08 11 Methocel E-3
(Hypermellose 2910) 10.58 7.06 14.12 Total 1117.80 745.20 1490.4
q.s. means quantity sufficient.
[0080] Levetiracetam 750 mg was sifted through s. s. sieve of mesh
40 and was then granulated with aqueous Polyvinyl pyrrolidone
solution and the granulated mass was dried at 45.degree. C. The
dried granules are sized through s. s. sieve of mesh 20 and these
granules were blended with Hypermellose 2208 and lubricated with
magnesium stearate, colloidal silicon dioxide and talc. The
lubricated granules were compressed into tablets.
[0081] The tablets as mentioned in the table 14, were coated with
mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl
Methylcellulose (E-3) and polyethylene glycol. The tablets were
coated to target weight gain of 3.5% w/w. The coated tablets were
cured at 65.degree. C. for 1 hr.
[0082] The functional coated tablets were further coated with
Opadry to a weight gain of 2.5% w/w of the functional coated
tablet.
Example 19
[0083] The extended release tablets of Examples 16-18 were tested
for dissolution of Levetiracetam using 900 ml of pH 6.8 phosphate
buffer as dissolution media at 37.degree. C. and in 40-mesh basket
(USP Type 1) at 100 rpm
[0084] The dissolution profiles are recorded in Table 15.
TABLE-US-00015 TABLE 15 Dissolution Profile Percentage
Levetiracetam dissolved Time(hrs) Ex. 16 Ex. 17 Ex. 18 1 20 16 14 2
35 31 29 3 46 44 39 4 55 53 49 6 69 67 63 8 79 77 72 10 87 86 80 12
93 91 86
[0085] A randomized two-treatment, two period, cross-over
pharmacokinetic study was conducted in eighteen healthy, adult,
male human subjects in both fast and fed conditions for the above
formulations and the data obtained was compared with the data of
Keppra.RTM. tablets.
Results
[0086] The following are a tabulation of the results of the study
in both fast and fed conditions. Comparison of data of the Tablet
of Example 16 and Keppra tablets in fasting conditions
TABLE-US-00016 TABLE 16 Parameter Unit Keppra .TM. Example 16 Cmax
ng/ml 31.49 .+-. 5.34 20.46 .+-. 2.08 Tmax Hrs 13.01 .+-. 0.55 9.88
.+-. 2.39 AUC (0-t) ng h/mL 469.98 .+-. 35.50 432.098 .+-. 55.11
AUC (0-inf) ng h/mL 516.99 .+-. 46.03 462.93 .+-. 65.25
[0087] Comparison of data of the invention of Example 16 and Keppra
tablets in fed conditions
TABLE-US-00017 TABLE 17 Parameter Unit Keppra .RTM. Example 16 Cmax
ng/ml 27.22 .+-. 3.43 20.50 .+-. 3.32 Tmax Hrs 12.59 .+-. 4.48
13.22 .+-. 2.81 AUC (0-t) ng h/mL 461.31 .+-. 57.66 450.12 .+-.
62.65 AUC (0-inf) ng h/mL 507.78 .+-. 75.20 497.27 .+-. 73.63
[0088] As can be seen from the above data, the
AUC.sub.fasted/AUC.sub.fed for example 16 is 0.96 for AUC.sub.(0-t)
and 0.93 for AUC.sub.(0-inf).
[0089] Although certain presently preferred embodiments of the
invention have been specifically described herein, it will be
apparent to those skilled in the art to which the invention
pertains that variations and modifications of the various
embodiments shown and described herein may be made without
departing from the spirit and scope of the invention. Accordingly,
it is intended that the invention be limited only to the extent
required by the appended claims and the applicable rules of
law.
* * * * *