FIELD OF THE INVENTION
Present invention in general relates to a stable pharmaceutical composition
comprising Tizanidine or its pharmaceutically acceptable salts, esters, solvates,
polymorphs, stereoisomers or mixtures thereof. In particular, the present invention
relates to a stable immediate release solid oral pharmaceutical composition
comprising methacrylic acid copolymer or its derivatives. The invention also provides
a process for manufacturing such composition.
BACKGROUND OF THE INVENTION
Tizanidine Hydrochloride is a centrally acting α2 adrenergic agonist and is
pharmaceutically used in management of spasticity.
Tizanidine Hydrochloride is chemically known as 5-chloro-4-(2-imidazolin-2-
ylamino)-2,1,3-benzothiadiazole monohydrochloride and is represented by the
following formula:
Tizanidine Hydrochloride is marketed in the USA as tablets and capsules under the
brand names ZANAFLEX®. Inactive ingredients in the ZANAFLEX® capsules
include hypromellose, silicon dioxide, sugar spheres, titanium dioxide, gelatin and
colorants.
3
US 3843668 discloses Tizanidine and its pharmaceutically acceptable acid addition
salts. Example 3 of patent publication discloses preparation of crystals of Tizanidine
having melting point of 221-223°C.
US 4053617 discloses a method of treating spastic conditions which comprises
administering a therapeutically effective amount of Tizanidine or its pharmaceutically
acceptable acid addition salts.
US 6455557 discloses a method of reducing somnolence in a patient receiving
Tizanidine therapy comprising administering to the patient a therapeutically effective
amount of Tizanidine in an immediate release multiparticulate pharmaceutical
composition with food.
US 2014/0341985 discloses an immediate release multi-particulate Tizanidine oral
dosage formulation which comprises a plurality of particles comprising from 2 mg to
12 mg of Tizanidine Hydrochloride and at least one pharmaceutically acceptable
excipient. The particles comprise immediate release beads comprising Tizanidine
Hydrochloride layered over non-pareil seeds. Tizanidine Hydrochloride immediate
release multi-particulates are prepared by spraying a solution of Tizanidine
Hydrochloride, hydroxypropyl methylcellulose and silicon dioxide in water over nonpareil
seeds (sugar spheres). The disclosed process is an expensive and time
consuming process which requires highly specialized equipment and trained
personnel. Moreover, control of the manufacturing process is difficult due to various
challenges associated with drug layering and control of critical process parameters.
Tizanidine Hydrochloride is approved for oral administration at low doses of 2 to
6mg. Low doses of Tizanidine Hydrochloride offers manufacturing challenges of
ensuring acceptable content uniformity of each of the low dose units. The small
amount of drug substance that is typically used for the manufacture of these low dose
4
units must be evenly distributed in a powder blend. Presently marketed capsule
formulation of Tizanidine Hydrochloride in the USA (ZANAFLEX®) is a multiparticulate
formulation which comprises layering of Tizanidine Hydrochloride over
non-pareil seeds. This is an expensive process, requires highly specialized equipment
and trained personnel. There exists a need in the pharmaceutical art to develop a
simple, reproducible, and cost-effective manufacturing process for preparing stable
pharmaceutical compositions of Tizanidine Hydrochloride capsules which offer
desired technical attributes such as comparable dissolution and bioequivalence with
respect to ZANAFLEX® capsules.
The present inventors developed a simple, reproducible, and cost-effective process for
preparing stable pharmaceutical compositions of Tizanidine Hydrochloride. Further,
pharmaceutical compositions prepared according to the manufacturing process of the
present invention exhibit desired technical attributes such as dissolution and
bioequivalence that is comparable to commercially marketed capsule formulation of
Tizanidine Hydrochloride.
SUMMARY OF THE INVENTION
One embodiment of the present invention relates to stable pharmaceutical
composition comprising Tizanidine or its pharmaceutically acceptable salts, esters,
solvates, polymorphs, stereoisomers or mixtures thereof which is bioequivalent to the
commercially available counterpart (ZANAFLEX® capsule) after oral administration.
In another embodiment, the present invention provides a process for the preparation
of stable pharmaceutical composition of Tizanidine or its pharmaceutically acceptable
salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof such that the
composition is bioequivalent to the commercially available ZANAFLEX® capsule
after oral administration.
5
Another embodiment of the present invention includes stable solid pharmaceutical
composition comprising Tizanidine Hydrochloride which is prepared by direct
compression, dry blending, dry granulation or wet granulation process.
Another embodiment of the present invention encompasses a stable pharmaceutical
composition comprising Tizanidine Hydrochloride which comprises at least one
pharmaceutically acceptable excipient selected from diluent, binder, surfactant,
lubricant, glidant and optionally other excipients.
In another embodiment of the present invention, the pharmaceutical composition is
substantially free of disintegrant and/or binder.
In another embodiment, the present invention includes a stable pharmaceutical
composition comprising Tizanidine Hydrochloride, wherein D90 is less than about 200
μm and D50 is less than about 80 μm.
Another embodiment of the present invention also provides a process for the
preparation of pharmaceutical composition of Tizanidine Hydrochloride, comprising
the steps of (a) blending a mixture of Tizanidine Hydrochloride and at least one
pharmaceutically acceptable excipient; (b) optionally preparing granules, milling the
granules, adding at least one lubricant and optionally other pharmaceutically
acceptable excipients to the granules and (c) filling the blend of step (a) or granules of
step (b) in capsules.
In another embodiment of the present invention, the granules present in the
pharmaceutical composition have bulk density more than or equal to 0.3g/cm3.
In yet another embodiment of the present invention, the granules present in the
pharmaceutical composition have tapped density more than or equal to 0.4g/cm3.
6
In another embodiment, at least 30% the granules present in the stable pharmaceutical
composition have a diameter of about 850 to about 250 μm [ASTM (American
Society for Testing and Materials) standards #20-60 mesh sieve]. Preferably, at least
40% the granules present in the pharmaceutical composition have a diameter of about
850 to about 250 μm [ASTM (American Society for Testing and Materials) standards
#20-60 mesh sieve]. More preferably, at least 50% the granules present in the
pharmaceutical composition have a diameter of about 850 to about 250 μm [ASTM
(American Society for Testing and Materials) standards #20-60 mesh sieve].
In another embodiment, stable pharmaceutical composition of the present invention is
placed inside capsule shell of size 00 to 5. Preferably, pharmaceutical composition of
the present invention is placed inside capsule shell of size 1 to 4.
In another embodiment, stable pharmaceutical composition of the present invention
exhibits a dissolution profile whereby more than 85% of the drug is released within
30 minutes.
In another embodiment, the pharmaceutical composition of the present invention is
stable for at least about six months at 40°C and 75% relative humidity.
In yet another embodiment of the invention, the stable pharmaceutical composition
comprises about 0.1 mg to about 40 mg of Tizanidine Hydrochloride.
In further embodiment, the present invention includes a method of using the
pharmaceutical composition comprising Tizanidine Hydrochloride in the
management of spasticity. In another embodiment of the invention, the stable
pharmaceutical composition is suitable for administration once daily or twice daily or
three times daily for the management of spasticity.
7
DETAILED DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following
detailed description of the invention and study of the included examples.
As used herein, the term “composition”, as in pharmaceutical composition, is
intended to encompass a drug product comprising Tizanidine or its pharmaceutically
acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, and
the other inert ingredient(s) (pharmaceutically acceptable excipients). Such
pharmaceutical compositions are synonymous with “formulation” and “dosage form”.
Pharmaceutical composition of the invention include, but is not limited to, granules,
tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets,
caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release
tablets, orally disintegrating tablets, pulsatile release tablets, timed release tablets,
delayed release, controlled release, extended release and sustained release tablets),
capsules (hard and soft or liquid filled soft gelatin capsules), pills, troches, sachets,
powders, microcapsules, minitablets, tablets in capsules and microspheres, matrix
composition and the like. Preferably, the pharmaceutical composition refers to tablets
and capsules. More preferably, the pharmaceutical composition refers to hard gelatin
capsules or HPMC based capsules. Most preferably, the pharmaceutical composition
refers to hard gelatin capsules.
The term "excipient" means a pharmacologically inactive component such as a
diluent, lubricant, surfactant, carrier, or the like. The excipients that are useful in
preparing a pharmaceutical composition are generally safe, non-toxic and are
acceptable for veterinary as well as human pharmaceutical use. Reference to an
8
excipient includes both one and more than one such excipient. Co-processed
excipients are also covered under the scope of present invention.
The term "bioequivalent" 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. In practice, two products are considered bioequivalent if the 90%
confidence interval of the Cmax, AUC, or, optionally, Tmax is within the range of
80.00% to 125.00%.
"Substantially free" as used herein refers to the pharmaceutical composition of
Tizanidine Hydrochloride, which does not contain binder and/or disintegrant.
According to a particularly preferred embodiment, the pharmaceutical composition is
substantially free of binder and/or disintegrant. In particular, the pharmaceutical
composition comprises less than 1% w/w of binder and/or disintegrant, by total
weight of the composition.
Unless otherwise stated the weight percentages expressed herein are based on the
final weight of the composition or formulation.
Bulk density, as used herein, refers to the ratio of the mass of an untapped powder
sample and its volume including the contribution of the interparticulate void volume.
Bulk density indicates mass of a powder material that can be filled in per unit volume.
Preferably, granules present in the pharmaceutical composition have bulk density
more than or equal to 0.3g/cm3.
Tapped density, as used herein, refers to the ratio of the mass of a tapped powder
sample and its volume. Tapped density of granules is determined using Electrolab tap
9
density tester (Model ETD 1020) where tapping is done at a rate of 500 to 1250
strokes per minute (SPM). Preferably, granules present in the pharmaceutical
composition have tapped density more than or equal to 0.4g/cm3.
The present invention relates to stable pharmaceutical composition of Tizanidine or
its pharmaceutically acceptable esters, salts, esters, solvates, polymorphs,
stereoisomers or mixtures thereof such that the composition is bioequivalent to the
commercially available ZANAFLEX® capsule after oral administration. Preferably,
salt of Tizanidine is Tizanidine Hydrochloride.
Tizanidine Hydrochloride in the present invention is used in an amount of about 0.1-
50% by weight with respect to total weight of the pharmaceutical composition.
Preferably, Tizanidine Hydrochloride in the present invention is used in an amount of
about 2-40% by weight with respect to total weight of the pharmaceutical
composition.
In another embodiment, the present invention includes particle size of Tizanidine or
its pharmaceutically acceptable esters, salts, esters, solvates, polymorphs,
stereoisomers or mixtures thereof, wherein D90 is less than about 200 μm and D50 is
less than about 80 μm.
Another embodiment of the present invention includes stable solid pharmaceutical
composition comprising Tizanidine Hydrochloride such that the composition is
bioequivalent to the commercially available ZANAFLEX® capsule and the
composition is prepared by direct compression, dry blending, dry granulation or wet
granulation process.
In another embodiment of the invention, the stable pharmaceutical composition
comprising Tizanidine Hydrochloride is prepared by using wet or dry granulation
process. Any pharmaceutically acceptable granulating solvent or mixture of
10
granulating solvents can be used for wet granulation. Suitable granulating solvents
include aqueous or organic solvents. Preferable granulating solvents include, but are
not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols
such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform,
dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and
combinations thereof. Preferably, the granulating solvent used during wet granulation
is water.
In another embodiment of the invention, wet granulation can be performed using
Rapid mixer granulator, Fluid bed granulator, Planetary mixer and the like; dry
blending can be performed in V-blender or key blender; and dry granulation can be
performed using roller compacter or slugging techniques or by any other method
known in the art.
Another embodiment of the present invention encompasses a stable pharmaceutical
composition comprising Tizanidine Hydrochloride such that the composition is
bioequivalent to the commercially available ZANAFLEX® capsule after oral
administration and comprises at least one pharmaceutically acceptable excipient
selected from diluent, binder, surfactant, lubricant, glidant and optionally other
excipients.
In another embodiment of the invention, the stable pharmaceutical composition is
substantially free of disintegrant and/or binder.
Diluents or fillers are substances which usually provide bulk to the composition.
Various useful fillers or diluents include, but are not limited to calcium carbonate
(Barcroft™, MagGran™, Millicarb™, Pharma- Carb™, Precarb™, Sturcal™,
Vivapres Ca™), calcium phosphate, dibasic anhydrous (Emcompress Anhydrous™,
Fujicalin™), calcium phosphate, dibasic dihydrate (Calstar™, Di-Cafos™,
11
Emcompress™), calcium phosphate tribasic (Tri-Cafos™, TRI- TAB™), calcium
sulphate (Destab™, Drierite™, Snow White™, Cal-Tab™, Compactrol™), cellulose
powdered (Arbocel™, Elcema™, Sanacet™), silicified microcrystailine cellulose,
cellulose acetate, compressible sugar (Di-Pac™), confectioner's sugar, dextrates
(Candex™, Emdex™), dextrin (Avedex™, Caloreen™, Primogran W™), dextrose
(Caridex™, Dextrofin™, Tab fine D-IOO™), fructose (Fructofin™, Krystar™),
kaolin (Lion™, Sim 90™), lactitol (Finlac DC™, Finlac MCX™), lactose
(Anhydrox™, CapsuLac™, Fast-Flo™, FlowLac™, GranuLac™, InhaLac™,
Lactochem™, Lactohaϊe™, Lactopress™, Microfme™, Microtose™, Pharmatose™,
Prisma Lac™, Respitose™, SacheLac™, SorboLac™, Super-Tab™, Tablettose™,
Wyndale™, Zeparox™), magnesium carbonate, magnesium oxide (MagGran MO™),
maltodextrin (C*Dry MD™, Lycatab DSH™, Maldex™, Maitagran™, Maltrin™,
Maltrin QD™, Paselli MD 10 PH™, Star-Dri™), maltose (Advantose 100™),
mannitol (Mannogem™, Pearlitol™), microcrystailine cellulose (Avicel PH™,
Celex™, Celphere™, Ceolus KG™, Emcocel™, Pharmacel™, Tabulose™,
Vivapur™), polydextrose (Litesse™), simethicone (Dow Corning Q7- 2243 LVA™,
Cow Coming Q7-2587™, Sentry Simethicone™), sodium alginate (Keltone™,
Protanal™), sodium chloride (Alberger™), sorbitol (Liponec 70-NC™, Liponic 76-
NCv, Meritol™, Neosorb™, Sorbitol Instant™, Sorbogem™), starch (Flufiex W™,
Instant Pure-Cote™, Melojeϊ™, Meritena Paygel 55™, Perfectamyl D6PH™, Pure-
Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet
White™), pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof.
Preferably, filler is used in an amount of about 1 - 90 % by weight. More preferably,
filler is used in an amount of at least 50% by weight.
Binders impart cohesiveness to formulation. Various useful binders include, but are
not limited to acacia, alginic acid (Satialgine H8™), carbomer (Pemulen™,
Ultrez™), carboxymethylcellulose sodium (Akucell™, Finnfix™, Tylose™),
ceratonia (Meyprofleur™), cottonseed oil, dextrin (Crystal Gum™, Primogran W™),
12
dextrose (Lycedex PF™, Roferose™), gelatin, guar gum (Meprogat™, Meyprodor™,
5 Meyprofm™), hydrogenated vegetable oil type 1 (Sterotex™, Dynasan
P[omicron]O™, Softisan 154™, Hydrocote™), hydroxyethyl cellulose
(Idroramnosan™, Liporamnosan™, Natrosol™), hydroxyethyhnethyl cellulose
(Tylopur MHB™, Tylose MB™, Tyiose MH™, Tylose 10 MHB™), hydroxypropyl
cellulose (Klucel™, Methocel™), low substituted hydroxypropyl cellulose,
hypromellose (Methocel™, Metolose™, Pharmacoat™, Tylopur™), magnesium
aluminium silicate (Magnabite™, Neusilin™, Pharmsorb™, Veegum™),
maltodextrin, maltose (Advantose 100™), methylcellulose (Benecel™, Methocel™,
Metolose™), microcrystalline cellulose (Avicel PH™, Ceoϊus KG™, Emcocel™,
Ethispheres™, Fibrocel™, Pharmacel™, Tabulose™, Vivapur™), polydextrose
(Litesse™), polyethylene oxide (Polyox™), polymethacrylates (Eastacryl 30D™,
Eudragit™, Kollicoat MAE 30DP™), povidone (Kollidon™, Plasdone™), sodium
alginate (Protanal™), starch (Instant Pure- Cote™, Melojel™, Meritena Paygel 55™,
Perfectamyl D6PH™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity
826™, Tablet White™), pregelatinised starch, stearic acid, sucrose and zein, or
mixtures thereof. Preferably, binder is optionally used in an amount of about 0-10 %
by weight.
Various useful disintegrants include, but are not limited to, alginic acid (Protacid™,
Satialgine H8™), calcium phosphate, tribasic (TRI-TAB™), carboxymethylcellulose
calcium (ECG 505™), carboxymethylcellulose sodium (Akucell™, Finnfix™,
Nymcel Tylose CB™), colloidal silicon dioxide (Aerosil™, Cab-O-Sil™, Wacker
HDK™), croscarmellose sodium (Ac-Di-Sol™, Pharmacel XL™, Primellose™,
Solutab™, Vivasol™), crospovidone (Kollidon CL™, Kollidon CL-M™,
Polyplasdone XL™), docusate sodium, guar gum (Meyprodor™, Meyprofin™,
Meyproguar™), low substituted hydroxypropyl cellulose, magnesium aluminun
silicate (Magnabite™, Neusilin™, Pharmsorb™, Veegum™), methylcellulose
(Methocel™, Metolose™), microcrystalline cellulose (Avicel PH™, Ceolus KG™,
13
Emcoel™, Ethispheres™, Fibrocel™, Pharmacel™, Vivapur™), povidone
(Kollidon™, Plasdone™) sodium alginate (Kelcosol™, Ketone™, Protanal™),
sodium starch glycolate, polacrilin potassium (Amberlite IRP88™), silicified
microcrystalline cellulose (ProSotv™), starch (Aytex P™, Fluftex W™, Melojel™,
Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure- Cote™, Pure-
Dent™, Purity 21™, Purity 826™, Tablet White™) or pre- gelatinized starch
(Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab
ST 200™, Spress B82O™, Starch 1500 G™, Tablitz™, Unipure LD™), or mixtures
thereof. Preferably, disintegrant is optionally used in an amount of about 0-10 % by
weight.
Lubricants are added to a pharmaceutical composition for ease in processing, to
prevent adhesion to the equipment during processing. Lubricants used in the
composition include, but are not limited to, calcium stearate (HyQual™), glycerine
monostearate (Imwitor ™ 191 and 900, Kessco GMS5 ™, 450 and 600, Myvaplex
600P™, Myvatex™, Rita GMS™, Stepan GMS™, Tegin™, Tegin™ 503 and 515,
Tegin 4100™, Tegin M™, Unimate GMS™), glyceryl behenate (Compritol 888
ATO™), glyceryl palmitostearate (Precirol ATO 5™), hydrogenated castor oil
(Castorwax MP 80™, Croduret™, Cutina HR™, Fancol™, Simulsol 1293™),
hydrogenated vegetable oil 0 type I (Sterotex™, Dynasan P60™, Hydrocote™,
Lipovol HS-K™, Sterotex HM™), magnesium lauryl sulphate, magnesium stearate,
medium-chain triglycerides (Captex 300™, Labrafac CC™, Miglyol 810™, Neobee
M5™, Nesatol™, Waglinol 3/9280™), poloxamer (Pluronic™, Synperonic™),
polyethylene 5 glycol (Carbowax Sentry™, Lipo™, Lipoxol™, Lutrol E™, Pluriol
E™), sodium benzoate (Antimol™), sodium chloride, sodium lauryl sulphate (Elfan
240™, Texapon Kl 2P™), sodium stearyl fumarate (Pruv™), stearic acid
(Hystrene™, ϊndustrene™, Kortacid 1895™, Pristerene™), talc (Altaic™,
Luzenac™, Luzenac Pharma™, Magsil Osmanthus™, 0 Magsil Star™, Superiore™),
sucrose stearate (Surfhope SE Pharma D-1803 F™) and zinc stearate (HyQual™) or
14
mixtures thereof. Preferably, lubricant is present in an amount of about 0.1-5% by
weight.
Glidants improve flowability and accuracy of dosing. Glidants used in the
composition include, but are not limited to, tribasic calcium phosphate (TRITAB
™), calcium silicate, cellulose, powdered (Sanacel™, Solka- Floc™), colloidal
silicon dioxide (Aerosil™, Cab-O-Sil M-5P™, Wacker HDK™), magnesium silicate,
magnesium trisilicate, starch (Melojel™, Meritena™, Paygel 55™, Perfectamyl
D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity
21™, Purity 826™, Tablet White™) and talc (Luzenac Pharma™, Magsil
Osmanthus™, Magsil Star™, Superiore™), or mixtures thereof. Preferably, the
glidant is used in an amount of about 0.1-15% by weight.
Pharmaceutically acceptable surfactants include, but are limited to both non-ionic and
ionic surfactants suitable for use in pharmaceutical dosage forms. Ionic surfactants
may include one or more of anionic, cationic or zwitterionic surfactants. Examples
include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate,
monopalmitate, monostearate or another ester of olyoxyethylene sorbitane, sodium
dioctylsulfosuccinate (DOSS), lecithin, stearyic alcohol, cetostearylic alcohol,
cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides,
poloxamer, or any other commercially available co-processed surfactant like
SEPITRAP® 80 or SEPITRAP® 4000 and mixtures thereof. Preferably, the surfactant
is used in an amount of about 0-5% by weight.
In another embodiment of the invention, polymers suitable for use in the present
invention include pH dependent as well as pH independent polymers.
In another embodiment of the invention, pH dependent polymers suitable for use in
the present invention include, but are not limited to, cellulose acetate phthalate
15
(CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate
(HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS),
hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose
acetate phthalate (HPMCAP), methylcellulose acetate phthalate (MCAP) and
methacrylic acid copolymers or its derivatives. Methacrylic acid copolymers or its
derivatives are available under various trade names such as EUDRAGIT®, Acryl-
EZE®, Eastacryl®, and Kollicoat® from Evonik Industries, Colorcon, Eastman
Chemical and BASF Fine Chemicals respectively. Preferred pH dependent
methacrylic acid copolymers or its derivatives suitable for use in the present invention
include anionic copolymers such as, but not limited to, Eudragit® L 100-55, Acryl-
EZE, Eudragit® L 30 D-55, PlasACRYL™ HTP20, Eudragit® L 100, Eudragit® L
12.5, Eudragit® S 100, Eudragit® S 12.5, Eudragit® FS 30 D, PlasACRYL™ T20 etc.
More preferably, suitable anionic methacrylic acid copolymers or its derivative
include Eudragit® L 100-55, Acryl-EZE and Eudragit® L 30 D-55. Preferably, the pH
dependent polymer is used in an amount of about 0.1-45% by weight.
In another embodiment of the invention, pH independent polymers suitable for use in
the present invention include, but are not limited to, alkylcelluloses, such as
methylcellulose, ethylcellulose; hydroxyalkylcelluloses, for example, hydroxymethyl
cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and
hydroxybutylcellulose; hydroxyalkyl alkylcelluloses, such as hydroxyethyl
methylcellulose and hydroxypropyl methylcellulose (hypromellose);
carboxyalkylcelluloses, such as carboxymethylcellulose; alkali metal salts of
carboxyalkylcelluloses, such as sodium carboxymethylcellulose; carboxyalkyl
alkylcelluloses, such as carboxymethyl ethylcellulose; carboxyalkylcellulose esters;
other natural, semi-synthetic, or synthetic polysaccharides, such as alginic acid, alkali
metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agaragar,
gum arabic, guar gum, xanthan gum, starches, pectins, such as sodium
carboxymethyl amylopectin, chitin derivates, such as chitosan, polyfructans, inulin;
16
polyacrylic acids and the salts thereof; polymethacrylic acids, and the salts thereof,
methacrylate copolymers; polyvinylalcohol; polyvinylpyrrolidone (povidone),
copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of
polyvinylalcohol and polyvinylpyrrolidone; polyalkylene oxides, such as
polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and
propylene oxide; and combinations thereof. Methacrylic acid copolymers or its
derivative suitable for use in the present invention include, but are not limited to,
Eudragit® RL PO, Eudragit® RL 100, Eudragit® RL 30 D, Eudragit® RL 12.5,
Eudragit® RS PO, Eudragit® RS 100, Eudragit® RS 30 D, Eudragit® RS 12.5,
Eudragit® NE 30 D, Eudragit® NE 40 D, Eudragit® NM 30 D etc. Preferably, the pH
independent polymer is used in an amount of about 0.1-45% by weight.
In another embodiment of the invention, the pharmaceutical composition is
formulated into solid oral pharmaceutical dosage forms. Solid oral pharmaceutical
dosage forms include, but are not limited to, tablets, capsules, powders, granules and
sachets. Preferably, the solid oral pharmaceutical dosage form is a tablet or capsule.
More preferably, the solid oral pharmaceutical dosage form is a capsule.
In yet another embodiment of the invention, the pharmaceutical composition
comprises about 0.1 mg to about 40 mg of Tizanidine Hydrochloride. Preferably, the
pharmaceutical composition comprises about 2 mg to about 18 mg of Tizanidine
Hydrochloride. More preferably, the pharmaceutical composition comprises about 2
mg to about 6 mg of Tizanidine Hydrochloride.
In another embodiment, at least 30% of the granules present in the pharmaceutical
composition have a diameter of about 850 to about 250 μm [ASTM (American
Society for Testing and Materials) standards #20-60 mesh sieve]. Preferably, at least
40% the granules present in the pharmaceutical composition have a diameter of about
850 to about 250 μm [ASTM (American Society for Testing and Materials) standards
17
#20-60 mesh sieve]. More preferably, at least 50% the granules present in the
pharmaceutical composition have a diameter of about 850 to about 250 μm [ASTM
(American Society for Testing and Materials) standards #20-60 mesh sieve].
Diameter of granules is determined using Retsch AS 200 magnetic sieve shaker at an
amplitude of 30 to 90 Hz with time interval between 5 to 30 minutes (Refer: USP 29
<786> Particle size distribution estimation by analytical sieving).
In another embodiment, pharmaceutical composition of the present invention is
placed inside capsule shell of size 1 to 4.
The capsule dosage form prepared by the above process can be subjected to in vitro
dissolution evaluation according to Test 711 "Dissolution" in the United States
Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md.,
2014 ("USP") to determine the rate at which the active substance is released from the
dosage form, and the content of the active substance can be determined in solution by
high performance liquid chromatography. When comparing the test and reference
products, dissolution profiles should be compared using a similarity factor (f2). The
similarity factor is a logarithmic reciprocal square root transformation of the sum of
squared error and is a measurement of the similarity in the percent (%) of dissolution
between the two curves.
f2 = 50 • log {[1 + (1/n)Σt=1
n (Rt - Tt)2]-0.5 • 100}
Two dissolution profiles are considered similar when the f2 value is equal to or greater
than 50.
In another embodiment, pharmaceutical composition of the present invention exhibits
more than 85% of drug release within 30 minutes in 500 ml of 0.01 N HCl (Office of
Generic Drugs dissolution database) using a USP II apparatus (paddle) at a
temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute.
18
Another embodiment of the present invention also provides a process for the
preparation of pharmaceutical composition of Tizanidine Hydrochloride, comprising
the steps of (a) blending a mixture of Tizanidine Hydrochloride and at least one
pharmaceutically acceptable excipient, (b) optionally preparing granules, milling the
granules, adding at least one lubricant and optionally other pharmaceutically
acceptable excipients to the granules and (e) filling the blend of step (a) or granules of
step (b) in capsules.
The process of the present invention besides being cost effective, also makes it
possible to prepare a pharmaceutical composition of Tizanidine Hydrochloride,
wherein the composition has desirable technical attributes such as comparable
dissolution and bioequivalence with respect to ZANAFLEX® capsules.
In another embodiment, pharmaceutical composition of the present invention
particularly capsule dosage form of present invention can be packaged in HDPE
bottles or blister packs. HDPE bottles may optionally contain desiccants.
Another embodiment of the present invention includes method of using the
pharmaceutical composition comprising Tizanidine Hydrochloride in the
management of spasticity.
As used herein, the term "about" means ± approximately 20% of the indicated value,
such that "about 10 percent" indicates approximately 08 to 12 percent.
Having described the invention with reference to certain preferred embodiments,
other embodiments will become apparent to one skilled in the art from consideration
of the specification. The invention is further defined by reference to the following
examples describing in detail method for the preparation and testing of Tizanidine
Hydrochloride pharmaceutical composition. It will be apparent to those skilled in the
art that many modifications, both to materials and methods, may be practiced without
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departing from the scope of the invention. Following examples are set out to illustrate
the invention and do not limit the scope of the present invention.
EXAMPLES
Example I
Tizanidine Hydrochloride capsule dosage form was prepared by dry granulation
process by using formula as given in Table 1:
TABLE 1
Ingredient Functional category Quantity (% w/w)
Tizanidine Hydrochloride Active Ingredient 3.00
Lactose Diluent 70.00
Stearic acid Lubricant 4.00
Methacrylic Acid - Ethyl
Acrylate Copolymer
Polymer 23.00
The processing steps involved in the manufacturing of capsule dosage form is given
below:
i) Tizanidine Hydrochloride, Lactose, Stearic acid and Methacrylic acid
copolymer were sifted through a suitable sieve.
ii) The sifted blend of step i) was compacted to prepare slugs.
iii) Slugs obtained in step ii) were milled to prepare granules.
iv) The granules obtained in step iii) were screened using suitable sieve.
v) Granules obtained from step iv) were lubricated with Stearic acid and filled
into hard gelatin capsules.
Example II
Tizanidine Hydrochloride capsule dosage form was prepared by dry granulation
process by using formula as given in Table 2:
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TABLE 2
Ingredient Functional category Quantity (% w/w)
Tizanidine Hydrochloride Active 3.00
Mannitol Diluent 75.00
Magnesium stearate Lubricant 3.00
Methacrylic Acid - Ethyl
Acrylate Copolymer
Polymer 19.00
The processing steps involved in the manufacturing of capsule dosage form is given
below:
i) Tizanidine Hydrochloride, Mannitol, Magnesium stearate and Methacrylic
acid copolymer were sifted through a suitable sieve.
ii) The sifted blend of step i) was compacted to prepare slugs.
iii) Slugs obtained in step ii) were milled to prepare granules.
iv) The granules obtained in step iii) were screened using suitable sieve.
v) Granules obtained from step iv) were lubricated with Magnesium stearate and
filled into hard gelatin capsules.
Example III
The standardized method and equipment for testing dissolution time is provided in
Office of Generic Drugs dissolution database. The dissolution profile of capsule
dosage form prepared using quantitative composition as given in Table 1 was
measured in 500 ml of 0.01 N HCl (Office of Generic Drugs dissolution database)
using a USP II apparatus (paddle) at a temperature of 37±0.5°C and a rotation speed
of 50 revolutions per minute. The dissolution test was conducted on the reference
formulation ZANAFLEX® capsules in comparison to a capsule dosage form as given
in Example 1. The dissolution data is provided in Table 3.
TABLE 3
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Time point
(min.)
% drug released
Reference Example I
5 75 71
10 95 95
15 97 97
20 98 97
30 97 97
f2 value --- 84
Since, both commercially available ZANAFLEX® capsules and capsule dosage form
prepared using quantitative composition as given in Table 1 exhibited more than 85%
of drug release within 15 minutes, dissolution profiles of the two formulations were
found to be similar and similarity factor (f2) was found to be more than 50.
Example IV
Capsule dosage form prepared in Example I was subjected to Accelerated stability
testing as per the ICH guidelines at temperature/relative humidity of 40°±2°C / 75%
±5% RH for 6 months. The capsule dosage form was placed in a high density
polyethylene (HDPE) bottle with induction sealing and analyzed for drug content by
High Performance Liquid Chromatography (HPLC) method. The prepared dosage
form was found to be stable and exhibited following assay values (in the Table 4):
TABLE 4
Study period Acceptable limits Amount of Tizanidine
Hydrochloride in the Capsule
dosage form
Example I
Initial 90% - 110% 98.5%
After six months 90% - 110% 95.0%
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Example V
A bioequivalence study comparing the capsule dosage forms prepared in Example I
(Test product, T) with commercially available Reference product ZANAFLEX®
capsules (Reference product, R) was performed in forty nine healthy adult human
subjects and plasma drug concentrations were determined at regular intervals after
dosing. The following parameters were calculated for test and reference product:
AUC0-t = Area under plasma drug concentration versus time curve, from time zero
(drug administration) to the last measurable concentration.
AUC0-inf = Area under the plasma drug concentration versus time curve, from time
zero to infinity.
Tmax = Time after dosing until the maximum measured plasma drug concentration.
Cmax = Maximum plasma drug concentration.
T/R (Test vs Reference) ratio was determined for the calculated pharmacokinetic
parameters and is tabulated in Table 5.
TABLE 5
Pharmacokinetic parameter T/R Ratio (%)
Cmax 96.63
AUC0-t 104.61
AUC0-inf 104.47
T/R ratio for AUC of about 100% indicates that the capsule dosage form prepared in
Example I shows similar mean pharmacokinetic parameters when compared against
commercially available reference product ZANAFLEX® capsules which establishes
that the capsule dosage form prepared in Example I was bioequivalent to the
commercially available Reference product ZANAFLEX® capsules.
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Many modifications of this invention can be made without departing from its spirit
and scope, as will be evident to those skilled in the art. The specific embodiments
described herein are provided by way of example only, and the invention is to be
limited only by the terms of the appended claims, along with the full scope of
equivalents to which such claims are entitled.
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WE CLAIM:
1. An immediate release solid oral pharmaceutical dosage form comprising
Tizanidine or its pharmaceutically acceptable salts, esters, solvates,
polymorphs, stereoisomers or mixtures thereof, wherein:
a) the dosage form comprises one or more methacrylic acid copolymer or its
derivatives
b) Not less than 80% by weight of the Tizanidine Hydrochloride is released
within 30 minutes after said dosage form is placed in a dissolution vessel
filled with 500 ml of 0.01 N Hydrochloric acid maintained at 37±0.5°C
and stirred at a paddle speed of 50 rpm using a USP Type II (paddle)
apparatus
2. An immediate release pharmaceutical capsule dosage form comprising
Tizanidine or its pharmaceutically acceptable salts, esters, solvates,
polymorphs, stereoisomers or mixtures thereof, wherein:
a) the dosage form comprises one or more methacrylic acid copolymer or its
derivatives
b) optionally the dosage form is substantially free of binder and/or
disintegrant
3. An immediate release capsule dosage form comprising Tizanidine or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers
or mixtures thereof, wherein:
a) the dosage form comprises one or more methacrylic acid copolymer or its
derivatives
b) the dosage form is stable for at least about six months at 40°C at 75%
relative humidity.
4. An immediate release pharmaceutical capsule dosage form comprising
Tizanidine or its pharmaceutically acceptable salts, esters, solvates,
polymorphs, stereoisomers or mixtures thereof, wherein:
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a) the dosage form comprises one or more methacrylic acid copolymers or its
derivatives
b) the dosage form is bioequivalent to the ZANAFLEX® capsule after oral
administration.
5. The pharmaceutical dosage form of claims 1-4, wherein the dosage form is
prepared by dry blending or direct compression or granulation process.
6. The pharmaceutical dosage form of claim 1-4, wherein the dosage form
comprises pharmaceutically acceptable excipient selected from at least one of
diluent, surfactant, lubricant, glidant, pH dependent polymers or pH
independent polymers.
7. The pharmaceutical dosage form of claim 1-4, wherein methacrylic acid
copolymer is selected from Eudragit® L 100-55, Acryl-EZE and Eudragit® L
30 D-55.
8. The pharmaceutical dosage form of claim 1-4, wherein the pharmaceutically
acceptable salt comprises Tizanidine Hydrochloride.
9. The pharmaceutical dosage form of claims 1-8, wherein Tizanidine or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers
or mixtures thereof is present in an amount ranging from about 0.1 mg to
about 40 mg.
10. A process for preparation of an immediate release pharmaceutical capsule
dosage form comprising Tizanidine or its pharmaceutically acceptable salts,
esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein the
composition comprises one or more methacrylic acid copolymers or its
derivatives, the process comprising:
(a) blending a mixture of Tizanidine Hydrochloride and at least one
pharmaceutically acceptable excipient;
(b) optionally preparing granules, milling the granules, adding at least one
lubricant and optionally other pharmaceutically acceptable excipients to the
granules; and
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(c) filling the blend of step (a) or granules of step (b) in capsules.