WO2017037742A1

WO2017037742A1 - Oral pharmaceutical composition of tizandine

Info

Publication number: WO2017037742A1
Application number: PCT/IN2016/050289
Authority: WO
Inventors: Nitin Bhalachandra Dharmadhikari; Yashoraj Rupsinh Zala; Rama Rao Kamala VENKATA
Original assignee: Sun Pharma Advanced Research Company Ltd.
Priority date: 2015-09-01
Filing date: 2016-09-01
Publication date: 2017-03-09

Abstract

An oral pharmaceutical composition comprising tizanidine or pharmaceutically acceptable salts thereof, as the sole active ingredient in admixture with a release modifying agent wherein the release modifying agent comprises atleast one release modifying hydrophobic non-polymeric material, and wherein the bioavailability of tizanidine or the pharmaceutically acceptable salt thereof is not affected by the presence or absence of food in a subject's gastrointestinal tract.

Description

ORAL PHARMACEUTICAL COMPOSITION OF TIZANIDINE

FIELD OF THE INVENTION

The present invention relates to an oral, pharmaceutical composition of a muscle relaxant, tizanidine.

BACKGROUND OF THE INVENTION

Tizanidine, is a potent, central-acting myotonolytic agent, for example for the treatment of spastic conditions of different etiology (neurological, inflammatory, and rheumatic), and muscle relaxant, that principally affects spinal polysynaptic reflexes. It is marketed in USA under the Trademark Zanaflex^® by Athena Neurosciences, Inc. in tablet form containing 4 mg tizanidine as tizanidine hydrochloride and also as a capsule in the 2 mg, 4 mg or 6 mg strengths. It is essentially completely absorbed and has a short half-life of about 2.5 hours, resulting in it having to be administered three or four times daily. The absolute oral bioavailability of tizanidine is approximately 40% due to extensive first pass metabolism in the liver. Zanaflex Capsules and Zanaflex^® tablets are bioequivalent to each other under fasting conditions, but not under fed conditions. The package insert of Zanaflex indicates that, the peak plasma concentrations of tizanidine occurred at 1.0 hours after dosing and had a half -life of 2 hours for both tablets and capsules. However, in the fed condition, the mean maximal plasma concentration was increased by approximately 30%, and the median time to peak plasma concentration was increased by 25 minutes, to 1 hour and 25 minutes. In contrast, two 4 mg capsules when administered with food, showed a 20% decrease in the maximal plasma concentration and the median time to peak plasma concentration was increased to 2 to 3 hours. The label also reveals that the C_max for the capsule in fed state is 66% the C_max for the tablet in fed state. Thus, both the Zanaflex^® dosage forms were shown to have food effect giving an increased absorption for both the tablets and capsules in fed state, and with a greater absorption for tablet (-30%) as compared to capsule (-10%). It is for these reasons that prescribers were warned to prescribe the tablets/capsules either without or with food and to stick to a particular regimen once initiated. These pharmacokinetic differences are known to result in clinically significant differences when switching administration of tablet and capsules in fed or fasted state. SUMMARY OF THE INVENTION

The present invention provides an oral pharmaceutical composition comprising tizanidine or pharmaceutically acceptable salts thereof, as the sole active ingredient in admixture with a release modifying agent wherein the release modifying agent comprises atleast one release modifying hydrophobic non-polymeric material, and wherein the bioavailability of tizanidine or the pharmaceutically acceptable salt thereof is not affected by the presence or absence of food in a subject's gastrointestinal tract.

Particularly, the present invention provides an oral pharmaceutical composition comprising tizanidine or pharmaceutically acceptable salts thereof, as the sole active ingredient in admixture with a release modifying agent sufficient to render the pharmaceutical composition suitable for once a day administration and wherein the release modifying agent comprises atleast one release modifying hydrophobic non-polymeric material and wherein the bioavailability of tizanidine or the pharmaceutically acceptable salt thereof is not affected by the presence or absence of food in a subject's gastrointestinal tract.

Particularly, the present invention provides an oral pharmaceutical composition comprising tizanidine or pharmaceutically acceptable salts thereof, as the sole active ingredient in admixture with a release modifying agent sufficient to render the pharmaceutical composition suitable for twice a day administration and wherein the release modifying agent comprises atleast one release modifying hydrophobic non-polymeric material and wherein the bioavailability of tizanidine or the pharmaceutically acceptable salt thereof is not affected by the presence or absence of food in a subject's gastrointestinal tract. DETAILED DESCRIPTION OF THE INVENTION

The phrase 'wherein the bioavailability of tizanidine or the pharmaceutically acceptable salt thereof is not affected by the presence or absence of food in a subject's gastrointestinal tract' as used herein mentioned means that either the oral bioavailability measured as ratio of area under the plasma concentration time profile curve under fed Vs fasted and the maximum plasma concentration (C_max) under fed Vs fasted state ranges between 0.7 to 1.25. Particularly, the ratios of any of the oral bioavailability parameters, ranges between 0.75 to 1.25. The term 'a release modifying agent sufficient to render the pharmaceutical composition suitable for once a day' as used herein means that when the oral pharmaceutical composition is tested for its in vitro dissolution using acidic medium, release of tizanidine or pharmaceutically acceptable salts thereof, is in the range of 15% to 30% at the end of 2 hours and 20 % to 35 % at the end of 4 hours, wherein when tested by in vivo studies the composition provides plasma levels suitable for once a day administration.

The term 'admixture'as used herein means that the drug and the release modifying agents are physically in contact with each other or are present in the composition in such a manner that the release of the drug is modified by the presence of the release modifying agents.

The term 'a release modifying agent sufficient to render the pharmaceutical composition suitable for twice a day' as used herein means that when the oral pharmaceutical composition is tested for its in vitro dissolution using acidic medium, release of tizanidine or pharmaceutically acceptable salts thereof, is in the range of 20 % to 35 % at the end of 2 hours and 30 % to 50 % at the end of 4 hours, wherein when tested by in vivo studies the composition provides plasma levels suitable for once a day administration. In order to determine relative bioavailability parameters such as maximum plasma concentration (Cmax), area under the plasma concentration time profile curve (AUC_0-t and AUCo-oo) a randomized crossover bioavailability study is conducted in a group of healthy adult volunteer subjects. In this study the volunteers are required to fast overnight for atleast 10 hrs and are administered the composition of the present invention in the fed and fasted state which is compared against a reference immediate release product. For the fasted treatment group, subjects after a supervised overnight fast swallow a single oral dose (lx 12mg tablet) with of water at ambient temperature, in the morning according to the randomization schedule of the present invention given as once a day administration under fed conditions. For the fed treatment group,after a supervised overnight fast for at least 10 hours, subjects swallow a single oral dose (lx 12mg tablet) with water at ambient temperature, 30 minutes after administration of high calorie high fat breakfast, in the morning according to the randomization schedule.For the reference immediate release tizanidine group, after a supervised overnight fast for at least 10 hours, subjects swallow 3 doses, a first oral dose (lx 4 mg tablet) of the assigned formulation with water in morning, according to the randomization schedule. The second dose (lx 4 mg tablet) is administered 6 hours apart from the first dose, the third dose (lx 4 mg tablet) is administered 6 hours apart from the second dose and 12 hours apart from the first dose. All volunteers are supervised for at least 10 hours prior to administration of the composition until 4 hours after first dosing. Later meals or snacks are served 4 hours after dosing and at appropriate time thereafter. Water is permitted ab-lib until 1 hour before each dosing and again 1 hour after each dosing. The blood samples of volunteers are collected at regular intervals from 0 to 36 hours and tizanidine level in the plasma is analysed by LC-MS/MS method. A graph of time vs plasma concentration of tizanidine is plotted. The maximum plasma concentration (C_max), area under the plasma concentration time profile curve (AUC_0-t and AUCo-oo) are determined for both fed and fasted states and the ratios of fed vs fasted are calculated. The oral pharmaceutical composition of the present invention comprises tizanidine or a pharmaceutically acceptable salt thereof as the sole active ingredient. It may be present in the form of a pharmaceutically acceptable salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate,hemisuccinate sesquihydrate. It may be present as a polymorph, hydrate, co-crystal, or solvate. When the hydrochloride salt of tizanidine is used, it is present in an amount of about 4 mg to 15 mg, more particularly it is 4 mg, 5 mg, 6 mg ,7 mg, 8 mg, 9mg, 10 mg, 11 mg, 12 mg,13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, per single unit of the oral pharmaceutical composition. In the preferred embodiment, tizanidine is present in an amount of 12 mg per unit of the oral pharmaceutical composition. Tizanidine or its pharmaceutically acceptable salt is present in an amount of 1.5 to 7.5 percent of the oral pharmaceutical composition that is 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5% of the total oral pharmaceutical composition. In one preferred embodiment, tizanidine or its pharmaceutically acceptable salt is present in amount of 6.5% by weight of the total pharmaceutical composition.

The release modifying hydrophobic non-polymeric material used in the oral pharmaceutical composition of the present, does not include, within its scope certain other hydrophobic materials that are generally used for other purposes such as those which do not function to modify the release of the drug. Examples of these other release modifying hydrophobic non-polymeric materials, include, but are not limited to, stearic acid, which functions as a lubricant in the oral pharmaceutical composition and does not modify the release characteristics of the drug. The release modifying hydrophobic non-polymeric material used as per the present invention includes, but is not limited to, fatty acids; lower alcohol fatty acid ester, glycerol fatty acid esters; acetylated glycerol fatty acid esters, lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters and reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols or mixtures thereof. Some of the release modifying hydrophobic non-polymeric materials used in the present invention may have a melting point in the range of 40- 100 °C. It is possible to use triglycerides as the release modifying hydrophobic non-polymeric material. The triglycerides suitable for the present invention are those which solidify at ambient room temperature. Examples of suitable triglycerides include, but are not limited to, Aceituno oil, almond oil, arachis oil, babassu oil, beeswax blackcurrant seed oil, borage oil, candlenut oil, canola oil Lipex 108 (Abitec), castor oil, Chinese vegetable tallow oil, cocoa butter, coconut oil, corn oil, cottonseed oil, crambe oil,cuphea species oil, evening primrose oil, grapeseed oil, groundnut oil, hemp seed oil, Illipe butter, Kapok seed oil, Linseed oil and menhaden oil, mowrah butter, mustard seed oil, oiticica oil, olive oil, Palm oil,Palm kernel oil,Peanut oil, Super Refined Peanut Oil (Croda),Poppy seed oil,Rapeseed oil,Rice bran oil,Safflower oil,Super Refined Safflower Oil (Croda),Sal fat,Sesame oil, Super Refined Sesame Oil (Croda) Shark liver oil, Super Refined Shark Liver Oil (Croda),Shea nut oil,Soybean oil Stillingia oil, Sunflower oil,Tall oil,Tea seed oil,Tobacco seed oil,Tung oil (China wood oil),Ucuhuba,Vernonia oil,Wheat germ oil,Super Refined Wheat Germ Oil (Croda) Hydrogenated castor oil,Castorwax,Hydrogenated coconutoil,Pureco 100 (Abitec),Hydrogenated cottonseed oil Dritex C (Abitec), Hydrogenated palm oil, Dritex PST (Abitec); Softisan 154 (Hiils), Hydrogenated soybean oil,Sterotex HM NF (Abitec); Dritex S (Abitec),Hydrogenated vegetable oil, Sterotex NF (Abitec); Hydrokote M (Abitec),Hydrogenated cottonseed and castor oil Sterotex K (Abitec), Partially hydrogenated soybean oil Hydrokote AP5 (Abitec),Partially hydrogenated soy and cottonseedApex B (Abitec) oil, Glyceryl mono-, di-, tri-behenate Compritol 888 Glyceryl tributyrate (Sigma), Glyceryl tricaproate (Sigma), Glyceryl tricaprylate (Sigma), Glyceryl tricaprate Captex 1000 (Abitec), Glyceryl triundecanoate Captex 8227 (Abitec) Glyceryl trilaurate (Sigma), Glyceryl trimyristate Dynasan 114 (Hiils), Glyceryl tripalmitate,Dynasan 116 (Hiils) Glyceryl tristearate Dynasan 118 (Hiils) Glyceryl triarchidate(Sigma), Glyceryl trimyristoleate(Sigma), Glyceryl tripalmitoleate (Sigma)

Glyceryl trioleate (Sigma), Glyceryl trilinoleate (Sigma), Glyceryl trilinolenate (Sigma), Glyceryl tricaprylate/caprate Captex 300 (Abitec); Captex 355 (Abitec) ;Miglyol 810 (Hiils); Miglyol 812 (Hiils)Glyceryl tricaprylate/caprate/laurate Captex 350 (Abitec), Glyceryl tricaprylate/caprate/linoleate Captex 810 (Abitec; Miglyol 818 (Hiils), Glyceryl tricaprylatekaprate/stearate Softisan 378 (Hiils); (Larodan) Glyceryl tricaprylate/laurate/stearate (Larodan), Glyceryl l,2-caprylate-3-linoleate (Larodan) Glyceryl l,2-caprate-3-stearate (Larodan), Glyceryl l,2-laurate-3-myristate (Larodan) Glyceryl l,2-myristate-3-laurate (Larodan), Glyceryl l,3-palmitate-2-butyrate (Larodan), Glyceryl l,3-stearate-2-caprate (Larodan), Glyceryl 1 ,2-linoleate-3-caprylate.

Apart from the release modifying hydrophobic non-polymeric material used, the oral pharmaceutical composition includes hydrophilic material as the release modifying agent in admixture with tizanidine, the sole active ingredient. Suitable, hydrophilic materials that may be used, include, but are not limited, to cellulose derivatives such as C_1-4 alkyl celluloses like hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, high viscosity hydroxypropyl methyl cellulose or mixtures thereof which may be swellable in nature. In one more preferred embodiment of the present invention, the release modifying hydrophilic material is high viscosity hydroxypropyl methyl cellulose in the range of 11250 to 21000 cps. In another embodiment the release modifying hydrophilic material is a mixture of two different grades of hydroxypropylmethyl celluloses, still more preferably a mixture of hydroxypropyl methyl cellulose K15M and hydroxypropyl methyl cellulose K100M, wherein the designation "M" indicates the viscosity of 1000 centipoise.

In one preferred embodiment, the release modifying hydrophobic non-polymeric material used is a combination of triglyceride and diglycerides in amounts sufficient to render the oral pharmaceutical composition suitable for once a day or twice a day administration. In certain embodiments, the triglyceride is a hydrogenated cotton seed oil and and the diglyceride is glyceryl dibehenate. It is possible to however, use the release modifying hydrophobic non- polymeric material alone. The ratio of the release modifying hydrophobic non-polymeric material to the active ingredient ranges from 1 : 2 to 3: 1. In the preferred embodiment the ratio of release modifying hydrophobic non-polymeric material to the active ingredient is about 1 : 1. In another preferred embodiment, the ratio of release modifying hydrophobic non-polymeric material to the drug is around 5:2. Alternatively, the amount of the release modifying hydrophobic non-polymeric material may be expressed in terms of the percentage of the composition of the Tizanidine containing layer. The release modifying hydrophobic material may be present in the range of 6 to 10 % by weight of the composition of the Tizanidine containing layer, rendering the oral pharmaceutical composition suitable for once a day administration. In specific embodiments, the hydrogenated vegetable oil may be present in a range of 1 to 10% i.e. 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10 %, preferably in the range of 2 to 8 % by weight of the composition of the Tizanidine containing layer.

Alternatively, the amount of the release modifying hydrophobic non-polymeric material may be expressed in terms of the percentage of the composition of the Tizanidine containing layer. The release modifying hydrophobic material may be present in the range of 1 % to 5 % by weight of the composition of the Tizanidine containing layer, rendering the oral pharmaceutical composition suitable for twice a day administration. In one preferred embodiment, the release modifying hydrophobic non-polymeric material is glyceryl behenate and is present in an amount of about 3 % to 10% i.e. 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7% by weight of the composition of the Tizanidine containing layer. In another embodiment, the release modifying hydrophobic non-polymeric material is a combination of hydrogenated vegetable oil and diglyceride and present in an amount of about 1 to 5% ie 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% by weight of the composition of the Tizanidine containing layer. The release modifying hydrophilic materials may be present in the range of 1 to 40 % by weight of the composition of the Tizanidine containing layer, ie 1%, 2%, 3%, 4%, 5%, 6% 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%,27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%38%, 39%, 40%, preferably in the range of 2 to 30% by weight of the composition of the Tizanidine containing layer, more preferably in the range of 3 to 20% by weight of the composition of the Tizanidine containing layer. In the preferred embodiment, the release modifying hydrophilic material is present in the range of 1 to 40 % by weight of the composition of the Tizanidine containing layer. Some embodiments,include,5,6,7,8,9, 10, 11 , 12, 15, 16, 17, 18, 19,20,21 ,22,23,24,25,26,27,28,29,30,31 ,32, 33,34,35,36,37,38,39 or 40 % by weight of the composition of the Tizanidine containing layer. In case of the oral pharmaceutical composition that is suitable for twice a day administration, the release modifying hydrophilic material is present in the range of 0.1 to 30 % by weight of the composition of the Tizanidine containing layer. The inventors of the present invention have found that, the release modifying agent comprising a combination of hydrophilic material and hydrophobic non-polymeric material advantageously give a fed to fasted ratio of maximum plasma concentration (C_max) and area under the plasma concentration time curve (AUC_0-t and AUCo-oo) in the range of 0.75 to 1.25.This indicates that that the oral bioavailability of tizanidine is not affected by the presence or absence of food in a subject's gastrointestinal tract. Compositions which do not contain the combination of hydrophilic material and hydrophobic non-polymeric material as the release modifying agent, and contain only hydrophilic material fail to give the desired fed to fasted ratio of the bioavailability parameters such as C_max, AUCo-t and AUCo-oo in the range of 0.75 and 1.25. For example, the composition containing hydrophilic material alone as the release modifying agent gave a C_max fed to fasted ratio of 0.64.Thus these compositions have different plasma profiles in the fed and fasted states manifesting as a food effect. The tizanidine containing composition in the form of the layer may further include an enteric polymer in admixture with Tizanidine. Suitable enteric polymers which can be used include, but are not limited to, cellulose acetate phthalate, cellulose acetate trimellitate methyl acrylate - methacrylic acid copolymers, methacrylic acid ethyl acrylate copolymers, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, methyl acrylate, methyl methacrylate and methacrylic acid copolymers. In one preferred embodiment, the enteric polymer is composed of an anionic copolymer based on methacrylic acid and ethyl acrylate available under the trade name of Eudragit^® LI 00-55. The enteric polymer may be present in the range of 0 to 10 % i.e 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% of the composition of the Tizanidine containing layer, preferably in the range of 1 to 5% of the composition of the Tizanidine containing layer. The ratio of the enteric polymer to the release modifying hydrophobic non-polymeric material is in the range of 3:5 to 1 :6. In one preferred embodiment, the ratio of enteric polymer to release modifying hydrophobic non-polymeric material is 1: 1.3. In another preferred embodiment, the ratio of enteric polymer to the release modifying hydrophobic non-polymeric material is 1:2.2.

In certain embodiments, the oral pharmaceutical composition is in the form of a compressed layer, it which the core is either unilamellar core or bilayer core. In certain embodiments, the core is a bilayer core with two layers stacked over one another, one layer contains composition containing tizanidine, as the sole active ingredient in admixture with a release modifying agent sufficient to render the pharmaceutical composition suitable for once a day administration and wherein the release modifying agent comprises atleast one release modifying hydrophobic non- polymeric material. Particularly, in certain embodiments, the oral pharmaceutical composition comprising tizanidine or pharmaceutically acceptable salts thereof, as the sole active ingredient is in admixture with a release modifying agent wherein the release modifying agent comprises atleast one release modifying hydrophobic non-polymeric material, and wherein the bioavailability of tizanidine or the pharmaceutically acceptable salt thereof is not affected by the presence or absence of food in a subject's gastrointestinal tract. In this embodiment the tizanidine oral pharmaceutical composition has an intragranular phase and an extragranular phase, wherein the intragranular phase comprises tizanidine or its pharmaceutically acceptable salt as the sole active ingredient and release modifying hydrophobic non-polymeric material and and release modifying hydrophilic material and an extragranular phase is free of release modifying hydrophobic non-polymeric material. The release modifying agent is present in an amount sufficient to render the pharmaceutical composition suitable for once a day or twice a day administration. The release modifying hydrophobic non-polymeric material suitable to render the composition for once a day administration is present in the range of 6 to 15% by weight of the tizanidine containing layer. The release modifying hydrophobic non-polymeric material suitable to render the composition for twice a day administration is present in the range of 1 to 5% by weight of the tizanidine containing layer. The release modifying hydrophilic material suitable to render the composition for once a day administration is present in the range of 6 to 30% by weight of the tizanidine containing layer. The release modifying hydrophilic material suitable to render the composition for twice a day administration is present in the range of 1 to 5% by weight of the tizanidine containing layer. In certain other embodiments, the oral pharmaceutical composition comprising tizanidine or pharmaceutically acceptable salts thereof, as the sole active ingredient is in admixture with a release modifying agent wherein the release modifying agent comprises atleast one release modifying hydrophobic non-polymeric material, and wherein the bioavailability of tizanidine or the pharmaceutically acceptable salt thereof is not affected by the presence or absence of food in a subject's gastrointestinal tract. In this embodiment the tizanidine oral pharmaceutical composition.is in the form of a layer having an intragranular phase and an extragranular phase, wherein the intragranular phase comprises tizanidine or its pharmaceutically acceptable salt as the sole active ingredient and a release modifying hydrophilic material and an extragranular phase comprises release modifying hydrophobic non-polymeric material and wherein the extragranular phase is free of release modifying hydrophilic material. In these embodiments the release modifying agent is present in an amount sufficient to render the pharmaceutical composition suitable for once a day or twice a day administration. The release modifying hydrophobic non-polymeric material suitable to render the composition for once a day administration is present in the range of 6 to 15%by weight of the tizanidine containing layer. The release modifying hydrophobic non-polymeric material suitable to render the composition for twice a day administration is present in the range of 1 to 5% by weight of the tizanidine containing layer. The release modifying hydrophilic material suitable to render the composition for once a day administration is present in the range of 10 to 45%by weight of the tizanidine containing layer. The release modifying hydrophilic material suitable to render the composition for twice a day administration is present in the range of 1 to 9% by weight of the tizanidine containing layer. The amounts of hydrophilic and hydrophobic release modifying agents are adjusted suitably to achieve a once a day or twice a day release profile. The ranges given are merely for the purpose of exemplification and in no way should limit the scope of the invention.

In one specific embodiment, one of the release modifying hydrophobic non-polymeric materials may be present as an admixture with tizanidine or its pharmaceutically acceptable salt, wherein the composition is prepared by wet granulation. In another embodiment, the composition may be prepared by melt granulation wherein the hydrophobic material is used in the molten state, prepared by melt granulation. In yet another embodiment, pharmaceutical composition may be prepared by making one phase such as granules of tizanidine or its pharmaceutically acceptable salt with other excipients and the release modifying hydrophobic non-polymeric material, is incorporated into the extragranular phase. Tizanidine or its pharmaceutically acceptable salt containing intragranular phase may be in the form of granules, extrudates, compacts and the like and the extragranular phase containing the the release modifying hydrophobic non-polymeric material may be present as an extragranular phase.

In one embodiment, the oral pharmaceutical composition in the form of a coated tablet, said coated tablet comprising:

A) a core comprising two or more layers stacked over each other, wherein the first layer comprises tizanidine or its pharmaceutically acceptable salt as a sole active ingredient in admixture with a release modifying agent sufficient to render the pharmaceutical composition suitable for once a day administration and wherein the release modifying agent comprises atleast one release modifying hydrophobic non-polymeric material and a swellable layer comprising swellable excipients, wherein the swellable layer is free of gelling excipients,

B) a water insoluble polymeric coat surrounding the core of A) having one or more defects, wherein upon contact with aqueous environment, the defect allows ingress of aqueous environment into the swellable layer, wherein at least one or more preselected portion of the coating containing the defect that is in immediate vicinity of the swellable layer is removed, but the remaining portion of the coating is not removed and thereby exposing the first layer to release tizanidine over extended period of time.

In another embodiment, the oral pharmaceutical composition in the form of a coated tablet, said coated tablet comprising:

A) a core comprising two or more layers stacked over each other, wherein the first layer comprises tizanidine or its pharmaceutically acceptable salt as a sole active ingredient in admixture with a release modifying agent sufficient to render the pharmaceutical composition suitable for once a day administration, the admixture comprising an intragranular phase comprising tizanidine or its pharmaceutically acceptable salt, release modifying hydrophilic material and release modifying hydrophobic non-polymeric material and an extragranular phase free of release modifying hydrophobic non -polymeric material and a swellable layer comprising swellable excipients, wherein the swellable layer is free of gelling excipients,

B) a water insoluble polymeric coat surrounding the core of A) having one or more defects, wherein upon contact with aqueous environment, the defect allows ingress of aqueous environment into the swellable layer, wherein at least one or more preselected portion of the coating containing the defect that is in immediate vicinity of the swellable layer is removed, but the remaining portion of the coating is not removed and thereby exposing the release tizanidine over extended period of time. In another embodiment, the oral pharmaceutical composition in the form of a coated tablet, said coated tablet comprising:

A) a core comprising two or more layers stacked over each other, wherein the first layer comprises tizanidine or its pharmaceutically acceptable salt as a sole active ingredient in admixture with a release modifying agent sufficient to render the pharmaceutical composition suitable for once a day administration, the admixture comprising an intragranular phase comprising tizanidine or its pharmaceutically acceptable salt, release modifying hydrophilic material, wherein the intragranular phase is free of release modifying hydrophobic non-polymeric material and an extragranular phase having one or more release modifying hydrophobic non-polymeric material and a swellable layer comprising swellable excipients, wherein the swellable layer is free of gelling excipients, B) a water insoluble polymeric coat surrounding the core of A) having one or more defects, wherein upon contact with aqueous environment, the defect allows ingress of aqueous environment into the swellable layer, wherein at least one or more preselected portion of the coating containing the defect that is in immediate vicinity of the swellable layer is removed, but the remaining portion of the coating is not removed and thereby exposing the first layer to release tizanidine over extended period of time.

The first layer, composition of the Tizanidine containing layer contains Tizanidine or its pharmaceutically acceptable salt in an amount of 4 to 15 mg i.e. 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg or 15 mg per unit of the solid dosage form, such as the tablet. In specific embodiments, Tizanidine is present in admixture with a release modifying agent which is a release modifying hydrophobic non-polymeric material. In addition, an enteric polymer may be present in the first layer. The release modifying hydrophobic non-polymeric material or enteric polymers and their preferred ranges that may be used in the present invention are already described herein before and in additional embodiments given below. Preferred examples of the release modifying hydrophobic non-polymeric material present in the composition of the Tizanidine containing layer may be selected from the group consisting of triglyceride ie glyceryl dibehenate, or a combination of triglyceride ie glyceryl dibehenate and hydrogenated vegetable oil ie hydrogenated cotton seed oil. In these embodiments, the release modifying hydrophobic non-polymeric material may be present in a range of 1 to 60% by weight of the first layer ie 1% ,2%, 3%, 4%, 5%, 6% 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%,27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%38%, 39%, 40%,%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% by weight of the drug containing layer, more preferably 2 to 50% ie , and most preferably in the range of 5 to 25% of the drug containing layer. In addition to the release modifying hydrophobic non-polymeric material, the drug containing layer may include hydrophilic material in admixture with tizanidine or its pharmaceutically acceptable salt. In this embodiment, both the hydrophilic and release modifying hydrophobic non-polymeric material act together to modify the release of the drug. In these particular embodiments, the release modifying hydrophobic non-polymeric material is present in the amount of 5 to 25% by weight of the composition of the Tizanidine containing layer and the hydrophilic material is present in the range of 10 to 20% of the composition of the Tizanidine containing layer. In yet another embodiment, the release modifying agent contains a combination of release modifying hydrophobic non-polymeric material, hydrophilic material and enteric polymer in admixture with tizanidine or its pharmaceutically acceptable salts. In these embodiments, the release modifying hydrophobic non-polymeric material is present in the range of 1 to 30% of the first layer, preferably in the range of 5 to 25% of the composition of the Tizanidine containing layer. The hydrophilic agent is present in the range of 10 to 25% of the first layer. The enteric polymer is present in the range of 1 to 5% of the composition of the Tizanidine containing layer. The composition of the Tizanidine containing layer may additionally contain other excipients such as hydrophilic material, buffers, diluents, binders, lubricants and disintegrants. The composition of the Tizanidine containing layer may also contain a binder. The binders which can be used in the present invention, are those well known in the art and include but are not limited to povidone, copolymerized povidone, hypromellose, various starches, sugars, gums, low molecular weight hydroxypropyl methylcellulose and hydroxypropylcellulose. Preferably, povidone is used as a binder. The binder may be present in the concentration of 0 to 25 % of the composition of the Tizanidine containing layer ie 0%, 0.5% 1% ,2%, 3%, 4%, 5%, 6% 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% of the composition of the Tizanidine containing layer, preferably present in the range of 2 to 10%, preferably around 5 to 10% of the composition of the Tizanidine containing layer. The diluents which may be used include, but are not limited to lactose, microcrystalline cellulose, starch, calcium hydrogen phosphate, sucrose and mannitol and the like may be used as diluent. The diluents are present in the range of 15 to 70% by weight of the composition of the Tizanidine containing layer ie 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%,27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%38%, 39%, 40%,%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% 61%, 623%, 63%, 64%, 65% 66%, 67%, 68%, 69%, 70% by weight of the composition of the Tizanidine containing layer, more preferably in the range of 25 to 60% by weight.

The swellable layer of the bilayer core in certain embodiments is devoid of any drug. The swellable layer comprises swelling excipients, gas generating agents, wicking agents and mixtures thereof and the layer is, preferably, free of any hydrogel or gelling material. Preferably the swellable excipient is one that can swell upon imbibing water to at least twice its original volume. The swelling excipient that may be used may be selected from the group comprising cross linked vinylpyrrolidone polymers such as crospovidone; cellulose and cellulose derivatives such as carboxyalkyl celluloses, low substituted hydroxypropyl cellulose, crosslinked carboxyalkylcellulose and their alkali salts; starch and starch derivatives such as pregelatinized starch, dried starch, sodium starch glycolate; resins such as polacrillin potassium (Amberlite IRP 88) and the like and mixtures thereof. Carboxyalkyl celluloses like carboxymethyl cellulose and its alkali salts, and in more preferred embodiments of the present invention crosslinked carboxyalkyl celluloses like crosslinked carboxymethyl cellulose, commonly known as croscarmellose, and its alkali salts may be used as the swellable hydrophilic polymers. The swellable excipient is preferably used in an amount ranging from about 2 % to about 50 % by weight of the swellable layer ie 2%, 3%, 4%, 5%, 6% 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%,27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%38%, 39%, 40%,%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50% by weight of the swellable layer. Preferably, the swellable excipient that may be used is present in an amount ranging from about 5 % to about 30 %, by weight of the swellable rupturable layer. In one preferred embodiment the swellable agent is crosslinked polyvinyl pyrrolidone and is present in a range of 10 to 25% by weight of the swellable layer.

Gas generating agents that may be used in the present invention include carbonates such as calcium carbonate, bicarbonates such as sodium or potassium bicarbonate, sulfites such as sodium sulfite, sodium bisulfite, or sodium metabisulfite, and the like. These salts may be used alone or in combination with an acid source as a gas generating couple. The acid source may be an edible organic acid, a salt of an edible organic acid, acidic components such as acrylate polymers, or mixtures thereof. Examples of organic acids that may be used include citric acid, malic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, ascorbic acid, glutamic acid, and their salts, and mixtures thereof.

The swellable, layer may further comprise a wicking agent in an amount ranging from about 0.5% to about 90% ie 0.5% 1% ,2%, 3%, 4%, 5%, 6% 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% , 26%,27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%38%, 39%, 40%,%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% 61%, 623%, 63%, 64%, 65% 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% 89% 90% by weight of the swellable layer of the composition, more preferably 0.5 to 15% by weight of the swellable layer of the coated tablet composition, most preferably in the range of 1 to 5% by weight of the swellable layer of the composition. Examples of wicking agents that may be used include, but are not limited to, colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, alumina, sodium lauryl sulfate, low molecular weight polyvinylpyrrolidone, bentonite, magnesium aluminum silicate (Veegum K) and the like and mixtures thereof. Preferably, the wicking agents used in the pharmaceutical composition of the present invention include cellulose and cellulose derivatives, colloidal silicon dioxide, and mixtures thereof. The swellable layer may comprise diluents having wicking action. In certain embodiments, of the present invention co-processed microcrystalline cellulose is used as a wicking agent. The microcrystalline cellulose is co- processed with silicon dioxide preferably colloidal silicon dioxide. Such a co-processed microcrystalline cellulose (silicified MCC) shows improved compressibility as compared to standard grades of microcrystalline cellulose. The silicified microcrystalline cellulose with varying amounts of silicon dioxide is commercially available under the grand name Prosolv^®. Typically the colloidal silicon dioxide content is about 2.5 % w/w. The most preferred embodiments of the present invention use silicified microcrystalline cellulose with 2.5 % w/w of colloidal silicon dioxide. These are available commercially under the brand name Prosolv SMCC^® 90 with a median particle size in the region of 90 μπι and Prosolv SMCC ^®50 with a median particle size in the region of 50 μπι. According to one embodiment of the present invention, the amount of silicified microcrystalline cellulose that may be used in the present invention may range from about 5 % w/w to about 90 % w/w, more preferably from about 25 % to about 85 % and most preferably from about 50 % to about 80 % by weight of the swellable layer.

In a more preferred embodiment of the invention, the swellable layer comprises a swellable excipient selected from cross linked polyvinyl pyrrolidone and cross linked carboxy methyl cellulose and a diluent having a wicking action for example, silicified microcrystalhne cellulose. Microcrystalline cellulose, sold under the trade name Avicel, is a non-fibrous cellulose powder commonly used in pharmaceutical tablet compositions as a binder-disintegrant. Other additives may include lubricants like stearic acid, palmitic acid, magnesium stearate, calcium stearate, talc, carnauba wax or the like. Silica flow conditioners or glidants may also be included. In the preferred embodiment the silicified microcrystalline cellulose is present in the range of 50 to 80%, colloidal silicon dioxide is present in the range of 1 to 5% and crosslinked polyvinyl pyrrolidone is present preferably in the range of around 10 to 25% by weight of the swellable layer. The swellable layer additionally may comprise other excipients such as surfactants, lubricants, and other excipients commonly used in the pharmaceutical art.

The core tablet comprising two or more layers stacked over each other, in which the first layer comprises tizanidine or its pharmaceutically acceptable salt and a release modifying agent and the swellable layer comprises swellable excipients, is coated with a water insoluble polymeric coating surrounding the core. A seal coat may be applied onto the core tablet before coating it with the water insoluble polymeric coating. The water insoluble polymeric coat surrounding the core has one or more defects, wherein upon contact with aqueous environment, the defect allows ingress of aqueous environment into the swellable layer, wherein at least one or more preselected portion of the coating containing the defect that is in immediate vicinity of the swellable layer is removed, but the remaining portion of the coating is not removed and thereby exposing the first layer to release tizanidine over extended period of time. The water insoluble polymeric coat surrounding the core has one or more defects. The defects may be either preformed passageway or formed in situ. In embodiments the defect is a preformed defect. It is created by drilling an orifice of specific dimensions. The defect may also be an indent, tear, cut or may be partial cut which makes the coating weak and susceptible to rupture due to the force exerted by the swellable layer composition, after it comes in contact with aqueous environment. Alternatively, the defect may be formed in situ. This may be achieved by having a water insoluble polymeric coating having one or more water soluble components. The water soluble components may include water soluble inorganic compounds and water soluble organic compounds. More specifically inorganic soluble compounds include, for example, sodium chloride, sodium bromide, sodium carbonate, potassium chloride, potassium sulfate, potassium phosphate, potassium nitrate, calcium phosphate, calcium nitrate, calcium chloride, and the like. More specifically, soluble organic compounds include, water soluble polymers such as water soluble cellulose polymers, polyols, for example polyhydric alcohol, polyalkylene glycol, polyglycol and the like. Organic compounds that may be used as water soluble components also includes glucose, sucrose, sorbitol, mannitol, lactitol, lactose, sodium benzoate, sodium acetate, sodium citrate and the like.

In one specific embodiment, the water insoluble polymer used in the coating is selected from cellulose derivatives such as cellulose acetate, ethyl cellulose and the like, alone or in admixture with a sufficient amount of one or more water-soluble polymers selected from methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and mixtures thereof, such that the properties of the semipermeable coating are modified, thereby allowing the coating to be removed partially upon contact with an aqueous environment.

In another embodiment, a coating may surround the bilayer by using water insoluble agents like cellulose derivatives such as cellulose acetate, ethyl cellulose nitrocellulose, polyvinyl acetate and the like alone and further drilling one or more defects to form a preformed defect i.e. an orifice of size 400 microns on one planar surface of the tablet. In another embodiment the defect may be formed in-situ in the aqueous environment of the gastrointestinal tract. In the preferred embodiment, the water-insoluble polymer used is ethyl cellulose. Ethyl cellulose is used to obtain the coating and get a weight gain of about 1 to 25% of the core tablet weight i.e. 1%, 2%, 3%, 4%, 5%, 6% 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% of the core tablet weight, preferably around 5 to 20% of the core tablet weight, more preferably 5 to 15% of the core tablet weight to get a functional coated tablet. In some embodiments, a mixture of ethyl cellulose and hydroxypropyl methylcellulose, or a mixture of ethyl cellulose and polyvinylpyrrolidone, may be used to obtain the coating. The tablet may then be further film coated with a polyvinyl alcohol based coating to get a weight gain of around 1 to 15% ie 1%, 2%, 3%, 4%, 5%, 6% 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% by weight of the functional coated tablet, preferably about 1 to 10%, most preferably in the range of 1 to 5% by weight of the functional coated tablet to get a top coated tablet.

The tablets may made be made by various processes known in the art such as melt granulation, wet granulation, dry granulation, direct compression. In one embodiment, when the hydrophobic agent is present intragranularly, in admixture with the drug. The oral pharmaceutical composition according to the present invention may be in the form of a powder, granules, compacts which may be either filled into hard gelatin capsule or compressed into tablets. Suitable embodiments of the present invention can be prepared by varying the ranges of the essential components in the preferred/most preferred ranges as described herein before.

The oral pharmaceutical compositions of the present invention were tested for dissolution in 0.1 N HC1 and in an aqueous medium having a pH of 4.5 measured by USP Type I method at 100 rpm in 900 ml aqueous medium at 37°C. It was seen from the dissolution study that the release modifying agent worked to retard the release of the drug to give a composition suitable for once a day administration of tizanidine by giving a 24 hour release. In one embodiment of the present invention an oral pharmaceutical composition comprising tizanidine or a pharmaceutically acceptable salt thereof in admixture with a release modifying agent comprising atleast one more release modifying hydrophobic non-polymeric material was tested for dissolution in 0.1 N HC1 and an aqueous medium having a pH of 4.5. In this embodiment the pharmaceutical composition provided an in vitro release of tizanidine or pharmaceutically acceptable salts thereof, in the range of 15 to 30% at 2 hours and a release in the range of 25 to 45% at 4 hours in 0.1 N HC1 or aqueous medium having a pH of 4.5.

The oral pharmaceutical compositions of the present invention were subjected to oral bioavailability determination under fed and fasted conditions. It was found that upon oral administration of the pharmaceutical composition, the bioavailability was not affected by the presence or absence of food in a subject's gastrointestinal tract and equivalent plasma levels were achieved.

While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.

EXAMPLE 1 /A

Preparation of the Tizanidine containing composition:

Intragranular phase: Tizanidine HC1 in the range of of 5 to 10 % by weight of the total composition of the layer was blended with hydrophilic component, hydroxypropyl methyl cellulose K15M CR grade in the range of 10 to 20 % by weight of the total composition of the layer, blend of release modifying hydrophobic non-polymeric material, glyceryl behenate and hydrogenated vegetable oil in the range of 5 to 20% by weight of the composition of the layer and essential binders and diluents were added to this mix and granules were prepared.

Extragranular phase: A, enteric polymer in the range of 2 to 10 % by weight, was mixed with lubricants and anti-adherent.

The mixture of the intragranular phase and the extragranular phase together formed the Tizanidine containing composition.

EXAMPLE 1/B

The Tizanidine containing composition was converted into a bilayer coated tablet. For this, the blend of the tizanidine containing composition was topped with a second, swellable separate layer. In order to prepare the second swellable layer, the super-disintegrant in the range of 50 to 80% by weight of the swellable layer, wicking agent in the range of 1 to 5% by weight of the swellable layer and swellable agent in the range of 10 to 25% by weight of the swellable layer were mixed with appropriate colour and lubricated with stearic acid and talc. This was further slugged using a suitable compression machine. The slugs were then milled and the milled granules further lubricated with stearic acid and talc. The slugs thus containing the first layer and the second, swellable layer of the bilayer core were compressed into tablets. The tablets were coated with a polyvinyl alcohol based seal coat which was then further coated with water insoluble polymer coating to get a functional coat and this functional coated tablet was further coated with polyvinyl alcohol based film coating to get a top coated tablet. Coated tablets were further drilled on the swellable excipient containing layer surface using suitable drilling bead. The in-vitro dissolution profile of the above example was carried out in a dissolution media of 0.1 N HCL and in aqueous medium of pH 4.5 followed by pH 6.8 to determine the in vitro release of tizanidine or a pharmaceutically acceptable salt thereof, as measured by USP Type I method at 100 rpm in 900 ml aqueous medium at 37°C Table 1: In vitro dissolution data of coated tablet composition of example 1/B

The composition of Example IB was tested for its oral bioavailability, in the fed and the fasted state. In order to determine that, a randomized, open label, three treatment, three period, six sequence, single dose, cross over, relative bioavailability study comparing composition of Example 1/B, 12 mg Tizanidine hydrochloride when administered under fasting and fed conditions and Zanaflex ' containing 4 mg Tizanidine hydrochloride (given three time a day at 6 hours interval) when administered under fasted condition in twelve healthy human adult subjects. In case of fasting volunteers, blood samples were collected before dosing and at different time points for 36 hours. All volunteers were supervised for at least 10 hours prior to administration of the composition until 4 hours after first dosing. Latter meals or snacks were served 4 hours after dosing and at appropriate time thereafter. Water was permitted ab-lib until 1 hour before each dosing and again q 1 hour after each dosing.

In case of fed state, after a supervised overnight fast for at least 10 hours, subjects swallowed single oral dose (1 x 12 mg oral composition of Example 1/B) with 240 ml of water at ambient temperature, 30 minutes after administration of high calorie high fat breakfast (900 ± 100 Kcal), in the morning according to the randomization schedule.

After a supervised overnight fast for at least 10 hours, subjects swallowed first oral dose (IX 4 mg) of Zanaflex^® , with 240 ml water at ambient temperature in the morning, according to the randomization schedule. The second dose (1 X 4 mg) tablet was administered 6 hours apart from the first dose with 240 ml of water. The third dose (1 X 4 mg) was administered 6 hours apart from the second dose and 12 hours apart from the first dose with 240 ml of water. Second and third dosing was done within 2 minutes of scheduled time.

The ratio of area under the plasma concentration time profile curve under fed Vs fasted and the maximum plasma concentration (C_max) under fed Vs fasted state were in the range of 0.75 to 1.25. The ratio of AUC ₀-t Fed/Fasted was 0.95, The ratio of AUC ₀-oo Fed/Fasted was 0.99 and the ratio of C_max Fed/Fasted was 1.07.

Based on these results, it is concluded that the oral bioavailability of tizanidine or the pharmaceutically acceptable salt thereof was not affected by the presence or absence of food in a subject's gastrointestinal tract.

EXAMPLE 2

Example 2 was prepared as per the procedure used in example 1 , but without the use of an enteric polymer in the Tizanidine containing composition layer of the bilayer core.

The in-vitro dissolution profile of the above example was carried out in a dissolution media of 0.1 N HCL and in aqueous medium of pH 4.5 followed by pH 6.8 to determine the in vitro release of tizanidine or a pharmaceutically acceptable salt thereof, as measured by USP Type I method at 100 rpm in 900 ml aqueous medium at 37°C. Table 2: In vitro dissolution data of coated tablets of example 2

It is seen from the dissolution study that the release modifying agent work to retard the release of the drug to give a tablet suitable for once a day administration of tizanidine.

EXAMPLE 3

The oral pharmaceutical composition in the form of coated bilayer tablets was prepared as per the procedure of example 1. The hydrophobic agent was glyceryl behenate instead of a mixture of glyceryl behenate and hydrogenated vegetable oil. The core tablets were prepared by wet granulation instead of melt granulation. Tizanidine hydrochloride, 12 mg was used and the release modifying hydrophobic non-polymeric material, which was glyceryl behenate is added extragranularly, i.e in the other phase outside the tizanidine containing phase.

The tablets prepared were subjected to dissolution studies in a USP Type I apparatus, at lOOrpm in 900 ml of 0.0 IN HC1. The dissolution results obtained were as follows: Table 3: In vitro dissolution data of coated tablets of example 3

The composition of Example 3 was tested for its oral bioavailability, in the fed and the fasted state.

The composition of Example 3 was tested for its oral bioavailability, in the fed and the fasted state. In order to determine that, a randomized, open label, three treatment, three period, six sequence, single dose, cross over, relative bioavailability study comparing composition of Example 1/B, 12 mg Tizanidine hydrochloride when administered under fasting and fed conditions and Zanaflex ' containing 4 mg Tizanidine hydrochloride (given three time a day at 6 hours interval) when administered under fasted condition in twelve healthy human adult subjects. In case of fasting volunteers, blood samples were collected before dosing and at different time points for 36 hours. All volunteers were supervised for at least 10 hours prior to administration of the composition until 4 hours after first dosing. Later meals or snacks were served 4 hours after dosing and at appropriate time thereafter. Water was permitted ab-lib until 1 hour before each dosing and again q 1 hour after each dosing.

The ratio of area under the plasma concentration time profile curve under fed Vs fasted and the maximum plasma concentration (C_max) under fed Vs fasted state were in the range of 0.75 to 1.25. The ratio of AUC _0-t Fed/Fasted was 0.76, the ratio of AUC _0-00 Fed/Fasted was 0.78 and the ratio of C_max Fed/Fasted was 0.96.

Claims

Claims:

1. An oral pharmaceutical composition comprising tizanidine or pharmaceutically acceptable salts thereof, as the sole active ingredient in admixture with a release modifying agent wherein the release modifying agent comprises atleast one release modifying hydrophobic non-polymeric material, and wherein the bioavailability of tizanidine or the pharmaceutically acceptable salt thereof is not affected by the presence or absence of food in a subject's gastrointestinal tract.

2. The oral pharmaceutical composition of claim 1, wherein the release modifying agent is sufficient to render the pharmaceutical composition suitable for once a day.

3. The oral pharmaceutical composition of claim 1, wherein the admixture comprises an intragranular phase comprising tizanidine or its pharmaceutically acceptable salt and release modifying hydrophobic non-polymeric material and release modifying hydrophilic material and an extragranular phase free of release modifying hydrophobic non-polymeric material.

4. The oral pharmaceutical composition of claim 1, wherein the admixture comprises an intragranular phase comprising tizanidine or its pharmaceutically acceptable salt and a release modifying hydrophilic material, wherein the intragranular phase is free of release modifying hydrophobic non-polymeric material and an extragranular phase comprising release modifying hydrophobic non-polymeric material.

5. An oral pharmaceutical composition of claim 2, wherein the release modifying hydrophobic non-polymeric material is selected from the group consisting of fatty acids; lower alcohol fatty acid ester, glycerol fatty acid esters; acetylated glycerol fatty acid esters, lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters and reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.

6. An oral pharmaceutical composition of claim 5, wherein the the release modifying hydrophobic non-polymeric material is glyceryl behenate or hydrogenated vegetable oil or mixtures thereof.

7. An oral pharmaceutical composition of claim 2, wherein the release modifying hydrophilic non-polymeric material is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, high viscosity hydroxypropyl methyl cellulose or mixtures thereof.

8. The oral pharmaceutical composition of claim 1, wherein the composition further comprises an enteric polymer.

9. The oral pharmaceutical composition of claim 1, wherein the tizanidine is present in an amount from 4 to 15 mg.

10. The oral pharmaceutical composition of claim 1, wherein the tizanidine is present in an amount of 12 mg.