FORM 2
THE PATENTS ACT 1970 (39 of 1970)
&
THE PATENTS RULE 2003
COMPLETE SPECIFICATION
(Section 10 and rule 13)
MODIFIED RELEASE DOSAGE FORMS OF BUPROPION"
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
having office at
Glenmark House,
HDO- Corporate Bldg,
Wing -A, B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099, INDIA
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to modified pharmaceutical release composition comprising Bupropion Hydrobromide and method of preparation thereof.
BACKGROUND OF THE INVENTION
Bupropion which is first discovered in US3819706, US3885046, is an antidepressant drug chemically unrelated to tricyclics, tetracyclics, selective serotonin re-uptake inhibitors (SSRIs), or other known antidepressant agents. Bupropion hydrochloride is commercially available in its Hydrochloride salt form under the tradename WELLBUTRIN®) and WELLBUTRIN® SR, ZYBAN®), WELLBUTRIN XL ®) out of which WELLBUTRIN® SR and WELLBUTRIN XL are sustained release versions. However recently Biovail markets in US APLENZIN® Tablets (174,348 & 522mg) for the treatment of major depressive disorder, which consist of a Hydrobromide sail of Bupropion i.e. Bupropion Hydrobromide. Biovail has a family of patent which covers one or other aspects of Bupropion Hydrobromide and its compositions.
US 7241805 describes a stable modified release bupropion hydrobromide tablet comprising: (a) core comprising (i)' bupropion hydrobromide, (ii) binder, and (iii) lubricant; (b) a controlled release polymeric coat which surrounds said core; and (c) a 3-CBZ degradation product. The tablet composition of patent US'805 has controlled levels of 3-CBZ which is known impurity associated with Bupropion.
Another patent US7563823 discloses controlled release composition comprising bupropion hydrobromide dispersed within a matrix. The patent describes enhanced stable matrix composition of bupropion hydrobromide as compared to composition containing Bupropion hydrochloride
US20080081068 filed by Biovail modified release tablet composition comprising a core of (i) bupropion hydrobromide in an amount of from 40% to 99% by weight of the tablet dry

weight; (ii) binder in an amount of from 0.25% to 25% by weight of the tablet dry weight; and (iii) lubricant in 'an amount of from 0.1% to 6% by weight of the tablet dry weight; and (b) a control-releasing coat.. The composition of patent US'1068 are said to be more stable than its bupropion hydrochloride counterparts.in view of 3-CBZ impurity.
Most prior art discloses use of release controlling polymeric material or osmotic material to modify release rate. The present invention relates to modified release dosage form comprising Bupropion & its pharmaceutically acceptable salts thereof, release regulating material and pharmaceutical excipients thereof. The present invention also relates to preparation of modified release dosage form comprising Bupropion & its pharmaceutically acceptable salts. By the use of release regulating material in modified release dosage form release rate of bupropion Hydrobromide can be extended even without the use of controlled release coat or osmotic dosage form.
SUMMARY OF THE INVENTION
The present invention provides, once a day modified release dosage form comprising Bupropion & its pharmaceutically acceptable salts thereof, release regulating material and pharmaceutical acceptable excipients.
In the preferred aspect, the present invention provides, once a day modified release dosage form comprising Bupropion Hydrobromide, one or more release regulating material selected from hydrophilic polymers, hydrophobic polymers mixtures thereof and pharmaceutical acceptable excipients.
In preferred aspect of the present invention provides once a day modified release dosage form comprising Bupropion Hydrobromide, release regulating material and pharmaceutical acceptable excipients coated with film coating polymers.
The present invention provides method of preparation of once a day modified release dosage form comprising sifting and mixing of Bupropion Hydrobromide. release regulating material & excipients. Spraying granulation solution of Cysteine Hcl and hydrophilic or hydrophobic

polymer to the mixture to form granules. Drying and milling of granules. Lubricate the granules with lubricant and compressed into tablets. Finally coat the tablets with film coating polymers.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The modified release dosage forms of the present invention comprises bupropion hydrobromide , release regulating material, and optionally stabilizers, pharmaceutically acceptable excipients.
The term "Modified release" as used herein, can be controlled release, sustained release, prolonged release and the like.
The term "modified release dosage form " as used herein is defined to mean a dosage form in which the bupropion and its salts is dispersed within a release regulating material , which matrix can be either insoluble, soluble, or a combination thereof.
The term "release regulating material" as used herein, is meant to any polymeric material which can retard or control or sustain release of drug from the dosage form. The term can be used interchangeably as release regulating polymers. The release regulating material can be either insoluble, soluble, or a combination thereof in which the rate of release is slower than that of an uncoated conventional or immediate release dosage forms. The release regulating polymers can be controlled release polymers, sustained release polymers, extended release, prolonged release and the like.
Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. Other terms are defined as they appear in the following description and should be construed in the context with which they appear.
The present invention provides a modified release dosage forms containing an effective amount of a bupropion HBr, release regulating material and at least one pharmaceutically

acceptable excipient. The amount of the bupropion HBr present in the modified release dosage forms can vary in an amount of from 40% to 90% by weight of the matrix tablet weight. The tablet can be coated with non-functional coating or an immediate release coating optionally containing a bupropion HBr. Non-functional coatings are coatings that do not affect drug release but which affect other properties (e.g., they enhance the physical appearance of the formulation).
In the present invention, a modified release dosage form is provided in which the kinetics of drug release from the core is dependent at least in part upon the diffusion and/or erosion properties of excipients within the composition.'
The present invention provides modified release dosage form comprising an effective amount of bupropion hydrobromide which is stable when stored for at least 3 months and/or at least 6 months at 40 degrees C. and 75% relative humidity ("accelerated storage conditions").
In other embodiments of the present invention, the bupropion salt can be in the form of its anhydrous, hydrated, and solvated forms, in the form of prodrugs, and in the individually optically active enantiomers. The bupropion salts can be amorphous or crystalline or amorphous solid dispersion.
The amorphous solid dispersion is solid dispersion of amorphous bupropion hydrobromide with carriers. Wherein the carrier comprises one or more povidone, gum, ethyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, lactose, polyhydric alcohol, polyethylene glycol, polyethylene oxide, pplyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol, or propylene glycol. The amorphous solid dispersion is prepared by lyophilisation or freeze-drying technique, a rotational drying, spray drying, fluid bed drying, flash drying, spin flash drying and the like.
The release regulating materials or release regulating polymers can be controlled release polymers, sustained release polymers, extended release, prolonged release or combinations thereof. These polymers are hydrophilic, hydrophobic polymers used alone or in combinations thereof. However, any pharmaceutically acceptable hydrophobic or hydrophilic

controlled release material which is capable of imparting modified release of the bupropion or salt thereof may be used in accordance with the present invention.
The term release regulating materials or release regulating polymers can be used interchangeably.
The Hydrophilic polymers include but not limited to hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC) or other cellulose ethers, polyoxyethylene, alginic acid, polyvinyl alcohols or combinations thereof. Preferred embodiment of the present invention contains hydrophilic polymers like hydroxypropylmethylcellulose, hydroxyethylcellulose (HEC). Most preferable hydrophilic polymer is HPMC K100MCR.
In at least one embodiment, the modified release dosage form comprises hydroxypropylmethylcellulose (HPMC), preferable HPMCK100MCR. Non-limiting examples of hydroxypropyl methylcelluloses that are commercially available include METHOCEL® E (USP type 2910), METHOCEL® F (USP type 2906), METHOCEL® J (USP type 1828), METHOCEL® K (USP type 2201), and METHOCEL® 310 Series, products of The Dow Chemical Company. The dosage form can comprise the different HPMC grades having different viscosities. Different HPMC grades can be combined to achieve the desired viscosity characteristics. For example, pharmaceutically polymer can comprise two HPMC polymers such as for example METHOCEL® K3 LV (which has a viscosity of 3 cps) and METHOCEL® K100M CR (which has a viscosity of 100,000 cps). In addition, the polymer can comprise two hydroxypropylcellulose forms such as KLUCEL® LF and KLUCEL® EF. In addition, the at least one polymer can comprise a mixture of a KLUCEL® and a METHOCEL®.
Hydroxypropyl Methylcellulose 2208, USP used in the examples, conforms to 19.0 to 24.00% methoxyl substitution and 7.0 to 12.0% hydroxypropoxyl substitution. The preferred nominal viscosity of 2% solution in water is not less than 50,000 centipoise.
In at least one embodiment of the invention the controlled release matrix dosage form may comprises a hydrophobic polymer such as ethylcellulose, acrylic acid derivatives such as

polyacrylic acid, Carbopol, polymethacrylate polymer such as EUDRAGIT® RSPO, RLPO, RL. RS, R, S. NE and E, acrylic acid polymer, methacrylic acid polymer. The release regulating material may comprise of wax material like but not limited to glyceryl behenate, glyceryl monostearate and the like. It may also contain other hydrophobic or hydrophilic controlled release material (release regulating material)
.In addition the present invention provides bupropion hydrobromide modified release dosage forms optionally coated with film coating polymers. Thereafter, the tablet (sometimes referred to as the core) is preferably film coated with a color coating such as Opadry Purple, Opadry Blue or Opadry White for identification, taste masking, and appearance purposes to provide a film coated tablet. The film coating does not substantially affect the release rate of the bupropion hydrobromide from the tablet and stability, since the coating is instant release which rapidly dissolves in the stomach. Preferably Opadry white AMB80W68912 is used for film coating
The dosage forms of the present invention comprise can be tablet, granules, capsule, Minitablets, spheroids, pellets.
The tablet also preferably includes as other ingredients, e.g, lubricating agents for ease in manufacture and fillers for ease of manufacturing and to bulk the tablet to provide the desired size. The dosage form may comprise of solubilizers, swelling agent.
In at least one embodiment of the invention the modifed release dosage form comprises at least one binder. Examples of binders include hydrogenated vegetable oil, castor oil, paraffin, cysteine hydrochloride, higher aliphatic alcohols, higher aliphatic acids, fatty acid esters,stearic acid, hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures thereof. Non-limiting examples of water-soluble polymer binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives, polyvinyl alcohol and water insoluble binders include ethylcellulose (ethocel 20cps), methacrylic acid polymer (eudragitNM30D)
In at least one embodiment of the invention the modifed release dosage form comprises at least one lubricant. Non-limiting examples of lubricants include stearic acid, hydrogenated

vegetable oils, stearyl alcohol, polyethylene glycol (MW 1450, suitably 4000, and higher), magnesium stearate, glyceryl monostearate, stearic acid, glycerylbehenate, polyethylene glycol and mixtures thereof.
In at least one embodiment of the invention the modifed release dosage form comprises at least one diluent, non-limiting examples of which include dicalcium phosphate, calcium sulfate, lactose or sucrose or other disaccharides, cellulose, cellulose derivatives, kaolin, mannitol, dry starch and the like.
In at least one embodiment of the invention the modified release dosage form may comprises of solubilizer. The solubilizer can act to increase the instantaneous solubility of the bupropion salt. The solubilizer can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants.
In at least one embodiment of the invention the modified release dosage form comprise additives for allowing water to penetrate into the core of the preparation. Examples of additives include polyethylene glycol (PEG); (e.g. PEG400, PEG1500, PEG4000, PEG6000, polyvinylpyrrolidone (PVP); D-sorbitol, xylitol, sucrose, Tween 80, magnesium chloride or the like.
In another embodiment of the invention the modified release dosage form comprises at least one disintegrant. Non-limiting examples of disintegrants for use in the matrix dosage form include croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose, sodium starch glycolate, starch, pregelatinized starch and the like, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose (e.g. Ac-Di-Sol), sodium starch glycolate (e.g. EXPLOTAB®). The disintegrant can be present in an amount of from 0 to 20% of the total weight of the core.
The modified release core is film coated with film coating materials like hydroxypropyl methylcellulose, polyvinyl alcohol, titanium dioxide, polyethylene glycol and the like. Suitable film coating solution used including Opadry.RTM. Purple YS-1-4845 is supplied by Colorcon, Inc., contains FD&C Red No. 40 Aluminum Lake, hydroxypropyl methylcellulose,

titanium dioxide, polyethylene glycol, polysorbate 80, and FD&C Blue No. 2 Aluminum Lake.
Opadry.RTM. Blue YS-1-4282 is supplied by Colorcon, Inc., contains FD&C Blue No. 1 Aluminum Lake, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and polysorbate 80. Opadry.RTM. White YS-1-7059 is supplied by Colorcon, Inc., contains hydroxypropyl methycellulose, titanium dioxide, and polyethylene glycol. Preferably Opadry white AMB80W68912 (aqueous moisture barrier film coating system, Colorcon TM) which is a polyvinyl alcohol-part hydrolysed, titanium dioxide (El71), talc, lecithin soya (E322) and xanthan gum.
The modified release dosage form of the present invention can be manufactured by methods known in the art. An example of a method of manufacturing modified release dosage form is peptization, hot melt granulation, melt-extrusion of a mixture containing the bupropion salt, hydrophobic polymer &/or hydrophilic polymer and optionally a binder, plasticizer, and other excipients. Other examples of methods of manufacturing controlled release matrices include wet granulation, dry granulation (e.g. slugging, roller compaction), direct compression; melt granulation, and rotary granulation.
The Modified release dosage form (tablets) of the present invention is prepared by blending particles of bupropion hydro bromide, microcrystalline cellulose and hydroxypropyl methylcellulose (Methocel.Kl00MCR.) to form an admixture of blended powders. A mesh sieve is used to screen the bupropion hydrobromide particles, cellulose particles and hydroxypropyl methylcellulose particles prior to blending the ingredients. Then the cysteine hydrochloride or glycine hydrochloride is dissolved in water to form a granulating solution. Also ethylcellulose or Eudragit dissolved in ethanol to form second granulating solution .Thereafter, the granulating solution is preferably sprayed onto the blended powders, which are then dried. A lubricant such as magnesium stearate is added, compressed into tablet core and film coated

In one of the embodiment the core is prepared by dissolving bupropion in binder solution and spraying the solution onto release regulating material and other excipients to form granules. The granules compressed after adding lubricants and film coated
Examples: Examples of forms of preferred solid pharmaceutical composition include a tablet or capsule. Preferably the pharmaceutical formulation of the present invention is a tablet. Such forms are prepared using standard procedures known in the art which involve admixing bupropion or a pharmaceutically acceptable salt thereof, the release regulating material with other optional excipients and compressing the mixture into a core. The core is coated with an seal layer. Optionally the core may be inserted into a capsule.
The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.
EXAMPLE 1: Matrix formulation of Bupropion Hydrobromide with hydrophilic polymer.

s.
No. Ingredient Qty/ Tab (mg)
DryM ix
I Bupropion Hydrobromide 174.00
2 Microcrystalline cellulose (Avicel PHI01) 35.00
3 Hydroxy Propyl Methyl Cellulose (HPMC K 100 MCR) 150.00
Binder
4 Cysteine HC1 20.00
5 Purified Water q.s.
6 Ethyl Cellulose (Ethocel 20cps) 10.0
7 Ethanol q.s.
Lubrication
8 Talc 3.00
9 Magnesium Stearate 8.00
Tablet Wt (mg) 400.0
Film coating (Non-functional)
10 Opadry White AMB 80W68912 15.0
Final Coated Tablet weight 415.0
Process:
Sift and Load ingredients Bupropion Hydrobromide, HPMC K100M & Avicel PH101 into
Fluid Bed Processor preheated for l0min. Dissolve 1-Cysteine HCI in purified water to form

solution & spray the solution to the blend of ingredients loaded in Fluid Bed Processor. Separately dissolve Ethocel 20cps in Ethanol to form solution which is sprayed over the blend of ingredients previously sprayed with 1-Cysteine HC1 to form granules. Dry and sift the granules. Blend the granules with talc, lubricate with magnesium stearate and compressed into tablets. Coat the compressed tablets with Opadry White AMB 80W68912.
EXAMPLE 2: Matrix formulation of Bupropion Hydrobromide with hydrophilic polymer & Ethyl cellulose extra granularly.

s.
No. Ingredient Qty/ Tab (mg)
Dry M ix
1 Bupropion Hydrobromide 174.00
2 Hydroxy Propyl Methyl Cellulose (HPMC K 100 MCR) 60.00
Binder
3 L-Cysteine HCI 15.00
4 Purified Water q.s.
5 Ethyl Cellulose (Ethocel 4cps) 10.00
6 Ethanol q.s.
Lubrication
7 Ethyl Cellulose (Ethocel l0cps) 26.00
8 Microcrystalline cellulose (Avicel PH102) 15.00
9 Low substituted Hydroxy propyl cellulose (L-HPC11) 18.00
10 Talc 3.00
11 Colloidal silicon dioxide (Aerosil 200) 3.00
12 Magnesium Stearate 9.00
Tablet Wt (mg) 333.00
Film coating (Non-functional)
13 Opadry White AMB 80W68912 10.0
Final Coated Tablet weight 343.00
Process:
Sift and Load ingredients Bupropion Hydrobromide & HPMC K100M into Fluid Bed Processor, preheated for lOmin. Dissolve 1-Cysteine HCI in purified water to form solution & spray the solution to the blend of ingredients loaded in Fluid Bed Processor. Separately dissolve Ethocel 20cps in Ethanol to form solution which is sprayed over the blend of

ingredients previously sprayed with 1-Cysteine HC1 to form granules. Dry and sift the granules. Blend the granules with Ethyl cellulose (10 cps), Microcrystalline cellulose, Low substituted Hydroxy propyl cellulose, Colloidal silicon dioxide & Talc, lubricate with magnesium stearate and compressed into tablets. Coat the compressed tablets with Opadry White AMB 80W6S912.
EXAMPLE 3: Matrix formulation of Bupropion Hydrobromide with Eudragit polymer

s.
No. Ingredient Qty/ Tab (mg)
Dry Mix
1 Bupropion Hydrobromide 174.00
2 Microcrystalline cellulose (Avicel PH101) 55.00
3 Methacrylic acid polymer (Eudragit RSPO/Eudragit RLPO) 110.00
Binder
4 Cysteine HC1 20.00
5 Purified Water q.s.
6 Methacrylic acid polymer (Eudragit NM30D) 30.00
Lubrication
7 Talc 3.00
8 Magnesium Stearate 8.00
Tablet Wt (mg) 400.00
Film coating (Non-functional)
9 Opadry White AMB 80W68912 15.0
Final Coated Tablet weight 415.0
Process:
Sift and Load ingredients Bupropion Hydrobromide, Eudragit RLPO/RSPO & Avicel PH101 into Fluid Bed Processor preheated for l0min. Dissolve 1-Cysteine HC1 in purified water to form solution & spray the solution to the blend of ingredients loaded in Fluid Bed Processor. Separately dissolve Eudragit NM30D in Ethanol to form solution which is sprayed over the blend of ingredients previously sprayed with I-Cysteine HCI to form granules. Dry and sift the granules. Blend the granules with talc, lubricate with magnesium stearate and compressed into tablets. Coat the compressed tablets with Opadry White AMB 80W68912.

EXAMPLE 4: Hot Melt Granulation with lipophilic polymer together with hydrophilic Matrix

S.No. Ingredient Qty/ Tab (mg)
Dry Mix
1 Bupropion Hydrobromide 174.00
2 Glyceryl Monostearate (Self emulsifying Grade) 30.0
3 Microcrystalline cellulose (Avicel PH101) 55.00
4 L-Cysteine HC1 20.00

Lubrication
5 Hydroxypropyl Methylcellulose (Methocel K100MCR) 50.0
6 Talc 3.00
7' Magnesium Stearate 8.00
Tablet wt (mg) 340.0
Film coating (Non-functional)
8 Opadry White AMB 80W68912 10.0
Final Coated Tablet weight 350.0
Process:
Sift and Load ingredients Bupropion Hydrobromide, Glyceryl Monostearate, Cysteine HCI & Avicel PH101 into Jacketed Rapid mixer granulator and mix for 10 mins. After mixing, circulate the hot water (Temp around 80°) into the jacketed RMG and continue mixing for 10-15 mins to form granules. Then circulate the normal water (Temp around 30°) and mix for another 5-10 min. Allow the granules to cool at room temperature. Sift & milled the granules. Blend the granules with Hydroxypropyl Methyl cellulose (Methocel K100M CR) and Talc. Lubricate with magnesium Stearate and compressed into tablets. Coat the compressed tablets with Opadry White AMB 80W68912.
EXAMPLE 5: Hot Melt Granulation with lipophilic polymer together with hydrophilic Matrix.

S.No. Ingredient Qty/ Tab (mg)
Dry Mix
I Bupropion Hydrobromide 174.00
2 Glyceryl Behenate 30.0

3 Microcrystalline cellulose (Avicel PH101) 55.00
4 L-Cysteine HC1 20.00

Lubrication
5 Hydroxypropyl Methylcellulose (Methocel K100MCR) 50.0
6 Talc 3.00
7 Magnesium Stearate 8.00
Tablet Wt (mg) 340.0
Film coating (Non-functional)
8 Opadry White AMB 80W68912 10.0
Final Coated Tablet weight 350.0
Process for example 5 would remain same as that of Example 4, with the only difference of addition of Gleceryl behenate instead of Glyceryl Monostearate
EXAMPLE 6. Matrix formulation with drug in dissolved state in binder

S. No. Ingredient Qty/ Tab (mg)
DryM ix
1 Microcrystalline cellulose (Avicel PH101) 50.00
2 Hydroxypropyl Methylcellulose (Methocel K100MCR) 40.00
3 Lactose Monohydrate ( Pharmatose 200 M) 48.00
Binder
4 Cysteine HC1 10.00
5 Purified Water q.s.
6 Bupropion Hydrobromide 174.00
7 Ethyl Cellulose / Povidone 50
8 Ethanol absolute q.s.
Lubrication
9 Hydroxypropyl Methylcellulose (Methocel K100MCR) 16
10 Talc 4.00
11 Magnesium Stearate 8.00
Tablet Wt (mg) 400.00
Film coating (Non-functional)
12 Opadry White AMB 80W68912 15.0
Final Coated Tablet weight 415.0

Process:
Sift and Load ingredients Hydroxypropyl Methylcellulose (Methocel K100M CR), Macrocrystalline cellulose (Avicel PH101) & Lactose Monohydrate ( Pharmatose 200 M) into Fluid Bed Processor preheated for l0min. Dissolve 1-Cysteine HC1 in purified water to form solution & spray the solution to the blend of ingredients loaded in Fluid Bed Processor. Separately dissolve Bupropion Hydrobromide, povidone (PVPK-30) & Ethyl cellulose (7cps) in ethanol to form solution which is sprayed over the blend of ingredients previously sprayed with 1-Cysteine HC1 to form granules. Dry and sift the granules. Blend the granules with Hydroxypropyl Methylcellulose (Methocel K100M CR) and Talc, lubricate with magnesium stearate and compressed into tablets. Coat the compressed tablets with Opadry White AMB 80W68912.

CLAIMS:
1. A modified release pharmaceutical composition comprising bupropion hydrobromide and one or more release regulating agents, and essentially free of release retarding coating
2. A modified release pharmaceutical composition according to claim 1, wherein the release regulating agent is a hydrophilic polymer.
3. A modified release pharmaceutical composition according to claim 2, wherein the hydrophilic polymer is hydroxylpropyhnethyl
cellulose.
4. A modified release pharmaceutical composition according to claim 1, wherein the release regulating agent is a hydrophobic polymer.
5. A modified release pharmaceutical composition according to claim 4, wherein the hydrophobic polymer is selected from ethyl cellulose, acryiates, glyceryl monostearate. glyceryl behenate.