WO2009087663A2

WO2009087663A2 - Oral controlled release coated tablet

Info

Publication number: WO2009087663A2
Application number: PCT/IN2008/000794
Authority: WO
Inventors: Nitin Balchandra Dharmadhikari; Yashoraj Rupsinh Zala
Original assignee: Sun Pharmaceutical Industries Ltd.
Priority date: 2007-11-30
Filing date: 2008-12-01
Publication date: 2009-07-16
Also published as: WO2009087663A3

Abstract

An oral, controlled release coated tablet having one or more surfaces, the coated tablet comprising: a core comprising a drug composition comprising metoprolol or its pharmaceutically acceptable salt, pH dependent polymer that is soluble in water at a pH below 5 and a copolymer of methacrylic acid and methacrylate and; a composition selected from a swellable composition and a reactive composition located in the immediate vicinity of one or more preselected surfaces and; a coating surrounding the core, wherein the coating is operable to be reliably removed fully from the one or more of the preselected surfaces of the tablet.upon contact with an aqueous environment, but not removed from at least one of the surfaces.

Description

ORAL CONTROLLED RELEASE COATED TABLET

The present invention relates to an oral, controlled release coated tablets comprising metoprolol or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION

Metoprolol succinate is a beta-selective adrenoceptor blocking agent. Once daily, extended release tablets of metoprolol succinate are currently available under the brand name Toprol XL^{® by} Astrazeneca. These tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet supposedly acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, respectively.

PCT publication number WO2007048233 (herein after referred to as publication ^ς233) discloses a sustained release composition of highly water soluble drugs like metoprolol succinate. It discloses the use of methacrylic acid copolymers to coat the granules of metoprolol succinate to decrease the drug's solubility. The coated granules are then mixed with a non eroding matrix.

While attempting to develop an oral controlled release composition of metoprolol, we found that the tablets comprising metoprolol and copolymer of methacrylic acid and methacrylate as the sole pH dependent polymer, had higher bioavailability than desirable in that they were not bioequivalent to Toprol XL^® in spite of the fact that the in vitro dissolution profile of the attempted composition was comparable to the Toprol XL^®

We surprisingly found that use of combination of a pH dependent polymer that is soluble in water at a pH below 5 and a copolymer of methacrylic acid and methacrylate, in the composition gave a desired bioavailability upon oral administration.

SUMMARY OF INVENTION

The present invention provides an oral, controlled release coated tablet having one or more surfaces, the coated tablet further comprising: a) a core comprising a drug composition comprising metoprolol or its pharmaceutically acceptable salt, pH dependent polymer that is soluble in water at a pH below 5 and a copolymer of methacrylic acid and methacrylate and; a composition selected from a swellable composition and a reactive composition located in the immediate vicinity of one or more preselected surfaces; and b) a coating surrounding the core, wherein the coating is operable to be reliably removed fully from the one or more of the preselected surfaces of the tablet upon contact with an aqueous environment, but not removed from at least one of the surfaces.

The present invention also provides an oral, controlled release coated tablet having one or more surfaces, the coated tablet further comprising: a) a core comprising a drug composition comprising metoprolol or its pharmaceutically acceptable salt, pH dependent polymer that is soluble in water at a pH below 5 and a copolymer of methacrylic acid and methacrylate and a composition selected from a swellable composition and a reactive composition located in the immediate vicinity of one or more preselected surfaces; and b) a coating surrounding the core, wherein the coating comprises water insoluble polymer(s) and leachable component(s) and is operable to be reliably removed fully from the one or more of the preselected surfaces of the tablet upon contact with an aqueous environment, but not removed from at least one of the surfaces,

DESCRIPTION OF THE FIGURES

Figure Ia shows the plot of mean plasma concentration of metoprolol versus lime in hours, when the subjects administered the coated tablets of example 1 in the fasted condition.

Figure I b shows the plot of mean plasma concentration of metoprolol versus time in hours, when the subjects administered the coated tablets of example 1 in the fed condition.

Figure 2a shows the plot of mean plasma concentration of metoprolol versus time in hours, when the subjects administered the coated tablets of comparative example 1 in the fasted condition.

Figure 2 b shows the plot of mean plasma concentration of metoprolol versus time in hours, when the subjects administered the coated tablets of comparative example 1 in the fed condition.

DETAILED DESCRIPTION OF THE INVENTION

The term 'bioavailability' as used herein means the rate and extent of absorption of the drug upon oral administration.

The term 'bioequivalent' as used herein means that the 90 % confidential interval of the ratios of the logarithmically transformed mean values of the pharmacokinetic parameters i.e AUC₀.i_nn_,, AUC₀.τ and peak plasma concentration C_max obtained upon oral administration of the coated tablets of the present invention, Io the logarithmically transformed mean values achieved upon oral administration of equal doses of commercially available Toprol XL^® by Astrazeneca, is within the range of 0.80 to 1.25.

The term 'preselected surfaces' as used herein means any surface of the tablet that is having the swellable or reactive composition in its immediate vicinity.

The present invention provides an oral, controlled release coated tablet having one or more surfaces, the coated tablet further comprising: a) a core comprising a drug composition comprising metoprolol or its pharmaceutically acceptable salt, pH dependent polymer that is soluble in water at a pH below 5 and a copolymer of methacrylic acid and methacrylate and a composition selected from a swellable composition and a reactive composition located in the immediate vicinity of one or more preselected surfaces and; b) a coating surrounding the core, wherein the coating is operable to be reliably removed fully from the one or more of the preselected surfaces of the tablet upon contact with an aqueous environment, but not removed from at least one of the surfaces.

The present invention also provides an oral, controlled release coated tablet having one or more surfaces, the coated tablet further comprising: a) a core comprising a drug composition comprising metoprolol or its pharmaceutically acceptable salt, pH dependent polymer that is soluble in water at a pH below 5 and a copolymer of methacrylic acid and methacrylate and a composition selected from a swellable composition and a reactive composition located in the immediate vicinity of one or more preselected surfaces and; b) a coating surrounding the core, wherein the coating comprises water insoluble polymer(s) and leachable component(s) and is operable to be reliably removed fully from the one or more of the preselected surfaces of the tablet upon contact with an aqueous environment, but not removed from at least one of the surfaces.

According to one embodiment of the present invention the oral, controlled release coated tablet comprises metoprolol succinate. The amount of metoprolol succinate that may be used ranges from about 10 mg to about 300 mg, preferably 20 mg to about 250 mg and most preferably from about 25 mg to about 200 mg per tablet.

The pH dependent polymer that is soluble below pH 5 used in the drug composition is a polymer prepared by polymerization of basic monomers with neutral monomers. Preferably the basic monomer is dimethyl aminoethyl methacrylate and the neutral monomer is a neutral methacrylate ester. According to the preferred embodiment, the polymer is poly (butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, methyl methacrylate), 1 :2: 1. In one embodiment of the present invention, the amount of the pH dependent polymer that is soluble below 5.0, ranges from about 1 % to about 30 %, preferably from about 5 % to about 20 % and most preferably about 15 % by weight of the drug composition.

The copolymer of methacrylic acid and methyl methacrylate that is used in the coated tablet of the present invention may be selected from the group consisting of copolymers of methacrylic acid and methyl methacrylate wherein the ratio of free carboxyl group to the ester group ranges from about 0.1: 0.9 to about 0.9: 0.1. Examples of the copolymer of methacrylic acid and methyl methacrylate that may be used include, but are not limited to, copolymers of methacrylic acid and methyl methacrylate in the ratio of about 1 : 1 (commercially available under the brand name of Eudragit L^®), copolymers of methacrylic acid and methyl methacrylate in the ratio of about 1 :2 (commercially available under the brand name of Eudragit S^® ). The anionic copolymer of methacrylic acid and methyl methacrylate are soluble in neutral to weakly alkaline pH and forms salts with alkalis. They are available as 12.5 % solution in propanol-2-ol without plasticizers; as a 12.5 % ready-to-use solution in propan-2-ol with 1.25 % dibutyl phthalate as plasticizer (Eudragit L 12.5 P and Eudragit S 12.5 P). In one preferred embodiment, the copolymer of methacrylic acid and methyl methacrylate is Eudragit L. The anionic copolymer may be present in the amount ranging from about 1 % to about 30 %, preferably from about 5 % to about 20 % and most preferably about 15 % by weight of the drug composition.

In one embodiment of the present invention, the drug composition may comprise pharmaceutically acceptable excipients that control the release of the drug. Such excipients are herein after referred to as "rate controlling excipients". These rate controlling excipients used in the present invention may be selected from hydrophilic polymers such as methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose; hydrophobic compounds such as ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, castor wax, carnauba wax, glycerol monostearate, stearyl alcohol, glycerol behenic acid ester, cetyl alcohol, natural and synthetic glycerides, waxes, fatty acids, hydrophobic polyacrylamide derivatives, hydrophobic methacrylic acid derivatives; vinyl pyrrolidone polymers such as polyvinylpyrrolidone and copolymers of vinyl pyrrolidone and vinyl acetate; alkylene oxide homopolymers; gums of plant, animal, mineral or synthetic origin; and mixtures thereof. The drug composition may comprise one or more of the rate controlling excipients in an amount ranging from about 2 % to about 90 % by weight of drug composition. One embodiment of the present invention uses hydroxypropylmethylcellulose polymers having viscosity ranging from about 50 to about 25,000 mPa.sec. Examples of the hydroxypropylmethylcellulose that may be used, include, but are not limited to, Methocels K4M, K15M and KlOOM and the like and mixture thereof. Preferably, hydroxypropylmethylcellulose having viscosity of 100,000 cps is used. The percentage of the hydroxypropyl methylcellulose may range from about 1 % to about 50 % by weight, preferably from about 5 % to about 15 % by weight of the drug composition.

According to the preferred embodiment of the present invention, the drug composition is either in the form of a single layer or multiple layers, which is further stacked with a swellable or reactive composition. The swellable or reactive composition may comprise optionally one or more drugs. According to the present invention, the swellable or reactive composition comprises excipients selected from the group consisting of swelling excipients, gas generating agents and wicking agents and mixtures thereof. Preferably the swellable excipient is one that can swell upon imbibing water to at least twice its original volume.

The swellable excipient used in the swellable composition 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 pre-gelatinized starch, dried starch, sodium starch glycolate; resins such as polacrillin potassium (Amberlite IRP 88) and the like and mixtures thereof. The swellable excipient is preferably used in an amount ranging from about 5 % to about 50 % by weight of the swellable composition. Preferably, the swellable excipient is used in an amount ranging from about 2 % to about 40 % by weight of the swellable composition, most preferably from about 10 % to about 25 % of the weight of the swellable composition.

One embodiment of the present invention uses gas generating agents in swellable or reactive composition. Examples of gas generating agents that may be used include, but are not limited to, 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 compounds 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.

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 coated tablets includes, but are not limited to, cellulose and cellulose derivatives, colloidal silicon dioxide, and mixtures thereof. The swellable composition may further comprise a wicking agent in an amount ranging from about 0.5 % to about 90 % by weight of the swellable composition.

In one embodiment of the present invention, the swellable composition comprises 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 % w/w. Certain embodiments of the present invention use silicified microcrystalline cellulose with 2 % 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 μm and Prosolv SMCC ^® 50 with a median particle size in the region of 50 μm.

According to one embodiment of the present invention, the amount of silicified microcrystalline cellulose that may be used ranges from about 5 % to about 90 %, preferably about 20 % to about 80 % by weight of the swellable composition.

In a more preferred embodiment of the present invention, the swellable composition comprises a swellable excipient selected from cross linked polyvinyl pyrrolidone, cross linked carboxy methyl cellulose and sodium starch glycolate and a diluent having a wicking action for example, silicified microcrystalline cellulose.

The drug composition and the swellable or reactive composition of the coated tablets of the present invention may comprise optionally conventional excipients such as diluents, binders, disintegrants, lubricants and the like.

According to the present invention, the coating is operable to be reliably removed fully from the one or more of the preselected surfaces of the tablet upon contact with an aqueous environment, but not removed from at least one of the surfaces. Such coatings have been described in our pending United States Patent application 2007- 0071816. Accordingly, the coating may be a defective coating which refers to coatings that are susceptible to rupture due to a weakness. The defect in the coating on the preselected surface may be made by creating a weakness in the coating by mechanical, chemical or electrical means, or by radiation. The defect may be created by designing a brittle coating, or a thin coating, or a brittle and thin coating or a porous coating on the preselected surface or surfaces. The defective coating may be provided with a mechanically or laser-drilled passageway, it is possible to create a defect may in the form of an apparent fault such as an indent or a tear or a cut or an etching, which beginning from the outer surface of the coating may penetrate only partially through the coating or may penetrate completely to the inner surface of the coating so as to form a passageway.

The defect may also be instantly created on the preselected surface by leaching of components of the coating upon contact with the aqueous environment. According to one preferred embodiment of the present invention, the core is coated with a coating composition comprising one or more water insoluble polymers. In one preferred embodiment, the coating comprises one or more Ieachable components. The leachable components may be selected from the group comprising water soluble organic compounds and water insoluble inorganic compounds or mixtures thereof. Examples of inorganic leachable compounds include, but are not limited to, sodium chloride, sodium bromide, sodium carbonate, potassium chloride, potassium sulfate, potassium phosphate, potassium nitrate, calcium phosphate, calcium nitrate, calcium chloride, and the like. The leachable organic compounds include, but are not limited to, 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 leachable components also includes glucose, sucrose, sorbitol, mannitol, lactitol, lactose, sodium benzoate, sodium acetate, sodium citrate and the like. The dry weight ratio of the water insoluble polymer to the leachable component ranges from about 10: 90 to about 90:10; more preferably from about 60:40 to about 40:60 and most preferably from about 70:30 to about 95: 5.

According to this embodiment of the present invention with a leachable component in the coating, upon contact with the aqueous environment, the leachable component(s) dissolves to form a micro porous coating. Water permeates through the coating and interacts with the swellable or reactive composition. Upon imbibing water, the swellable composition or the reactive composition swells or reacts causing the coating on the surface in it's immediate vicinity to be removed. The drug composition is exposed to the aqueous environment. A control on the release of the metoprolol is obtained by designing into the system an exposure to aqueous environment by removal of the coating from only a very limited surface area. The coating is removed only from the preselected surface or surfaces without a substantial delay.

Examples of water insoluble polymers that may be used include, but are not limited to, ethyl cellulose, cellulose acetate, polyvinyl acetate, nitrocellulose, butadiene styrene copolymers, and water insoluble methacrylate copolymers and hydroxypropyl methyl cellulose acetate succinate and the like and mixture thereof. According to this embodiment of the present invention with a leachable component in the coating, the coating is applied to the core of the tablet to a weight gain of about 5 % to about 20 % by weight of the core, preferably from about 8 % to about J 8 % by weight of the core tablet.

According to the present invention, the coating comprises one or more plasticizers. The plasticizers may be those that are conventionally used in the pharmaceutical art. These may be hydrophilic or hydrophobic in nature. Examples of hydrophilic plasticizer that may be used in the coating, include, but are not limited to, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, polyethylene glycol 6000, polysorbate 80, glycerol and the like and mixtures thereof. Examples of hydrophobic plasticizer that may be used in the coating include, but are not limited to, dibutyl sebacate, diethyl sebacate, diethyl phthalate, vegetable and mineral oil, glyceryl tributyrate and the like and mixtures thereof. More preferably, the plasticizer is a mixture of hydrophobic and hydrophilic plasticizers. In a particular embodiment wherein the coating comprises ethyl cellulose as the water insoluble polymer, the hydrophobic plasticizer is dibutyl sebacate and the hydrophilic plasticizer is triethyl citrate, preferably in the ratio of about 5: 1. More particularly, the percent of dibutyl sebacate by weight of ethyl cellulose is about 5 % and the percent of triethyl citrate is about 25 % by weight of ethyl cellulose.

The examples that follow are provided as illustrations and do not limit the scope of the present invention. Example 1

The drug composition layer and the swellable composition layers contents and its amounts are given in table 1. Metoprolol succinate, hydroxypropyl methyl cellulose, lactose, povidone and Eudragit E were mixed and granulated. The granules were dried. The dried granules of the drug composition were mixed with Eudragit L- 100-55 and the blend was lubricated with talc, magnesium stearate and colloidal silicon dioxide. The ingredients of the swellable composition was mixed and converted into slugs. The slugs of the swellable composition (62 mg) and the drug composition blend (138 mg) were compressed together to get bilayer core.

The bilayer core is coated with a coating composition as given in table 2. The coated tablets are further coated with Opadry coating to a weight gain of about 3 %.

Table 1

Table 2

applied in the form of Aquacoat ECD 30 which is an aqueous dispersion containing ethyl cellulose (27 % w/v), sodium lauryl sulphate 1 % w/w and cetyl alcohol 2 % w/v in water

Example 2

The bioavailability of the coated tablets prepared according to Example 1 and that of Toprol^® XL 50 mg ER tablets were studied in both fasting and fed condition. A single-dose, open label, randomized, comparative and two-way crossover study, with a seven-day washout period, was undertaken for the same.

Healthy male volunteers (n=number of volunteers, n=66 for fed state and n=69 for fasting state) were enrolled for two-way crossover study. The subjects were fasted overnight before dosing and for 4 hours thereafter. Drinking water was prohibited 2 hours before dosing and 2 hours thereafter, but was allowed at all other times. Standard meals were provided at 4, 6 and 8 hours after dosing and at appropriate times thereafter. Meal plans were identical for both the periods. In fed state subjects were give high fat breakfast before 30 minutes of dosing.

Subjects received a single tablet prepared according to Example 1 (50 mg) with 240 ml of drinking water at ambient temperature as the test medication, and a single oral dose of Toprol XL^® (50 mg metoprolol) also with 240 ml of drinking water at ambient temperature as the reference medication.

The mean plasma concentrations of metoprolol obtained upon oral administration of the coated tablets were plotted against time (post dose) in hour. Figure I a and Figure Ib show that the plasma levels obtained by pharmaceutical tablets prepared according to Example 1 in fed and fasting conditions respectively, are comparable to the Toprol XL^® tablets. Comparative Example 1

The drug composition layer and the swellable composition layer were prepared according to the following formulas. Metoprolol succinate, hydroxypropyl methyl cellulose, lactose and povidone were mixed and granulated. The granules were dried. The dried lubricated granules of the metoprolol succinate were mixed with Eudragit L-100-55 and hydroxymethylpropyl cellulose (viscosity 3000-5600). The swellable composition was converted into slugs. The slugs of the swellable composition (79 mg) and the drug composition (146 mg) were compressed together to make a bilayer compressed core.

The bilayer core is coated with the Aquacoat EC30D and a mixture of sodium lauryl sulphate, triethyl citrate, hydroxypropyl methyl cellulose low viscosity, polyethylene glycol 400 and polyethylene glycol 8000. The coated core is further coated with Opadry coating to a weight gain of about 3 %.

Table 3

Table 4

Comparative Example 2

The bioavailability of the oral coated tablets of metoprolol prepared according to the comparative example 1 and that of Toprol^® XL 50 mg ER tablets were studied in both fasting and fed condition. A single-dose, open label, randomized, comparative and two-way crossover study, with a seven-day washout period, was undertaken for the same.

Healthy male volunteers were enrolled for two-way crossover study. The subjects were fasted overnight before dosing and for 4 hours thereafter. Drinking water was prohibited 2 hours before dosing and 2 hours thereafter, but was allowed at all other times. Standard meals were provided at 4, 6 and 8 hours after dosing and at appropriate times thereafter. Meal plans were identical for both the periods. In fed state subjects were give high fat breakfast before 30 minutes of dosing. Subjects received a single tablet of metoprolol prepared according to Comparative Example 1 (50 mg) with 240 ml of drinking water at ambient temperature as the test medication, and a single oral dose of Toprol XL^® (50 mg metoprolol) also with 240 ml of drinking water at ambient temperature as the reference medication.

The mean plasma concentration of metoprolol obtained after administration of the coated tablets of comparative example 1, were plotted against time (post dose) in hour. Figure 2 (a) and Figure 2 (b) show that the plasma levels obtained by the coated tablets prepared according to comparative Example 1, in fed and fasting conditions respectively, were not comparable to Toprol XL^® tablets.

Claims

Claims:

1. An oral, controlled release coated tablet having one or more surfaces, the coated tablet comprising: a) a core comprising a drug composition comprising metoprolol or its pharmaceutically acceptable salt, pH dependent polymer that is soluble in water at a pH below 5 and a copolymer of methacrylic acid and methacrylate and a composition selected from a swellable composition and a reactive composition located in the immediate vicinity of one or more preselected surfaces and; b) a coating surrounding the core, wherein the coating is operable to be reliably removed fully from the one or more of the preselected surfaces of the tablet upon contact with an aqueous environment, but not removed from at least one of the surfaces.

2. An oral, controlled release coated tablet as claimed in claim 1 wherein the pH dependent polymer that is soluble below 5 is a polymer prepared by polymerization of basic monomers with neutral monomers.

3. An oral, controlled release coated tablet as claimed in claim 2 wherein the basic monomer is dimethyl aminoethyl methacrylate.

4. An oral, controlled release coated tablet as claimed in claim 2 wherein the neutral monomer is a neutral methacrylate ester.

5. An oral, controlled release coated tablet as claimed in 2 wherein the polymer is poly (butyl methacrylate, (2- dimethyl aminoethyl) methacrylate, methyl methacrylate), 1:2: 1.

6. An oral, controlled release coated tablet as claimed in claim 1 wherein the amount of the pH dependent polymer that is soluble in water at a pH below 5 ranges from about 5 % to about 20 % by weight of the drug composition.

7. An oral, controlled release coated tablet as claimed in claim 1 wherein the amount of a copolymer of methacrylic acid and methacrylate ranges from about 5 % to about 20 % by weight of the drug composition.

8. An oral, controlled release coated tablet as claimed in claim 1 wherein the drug composition comprises one or more hydrogel polymer selected from the group comprising of cellulose derivatives, gums, aiginic acid and its derivatives, polyacrylic acid, starch and its derivatives and mixtures thereof.

9. An oral, controlled release coated tablet as claimed in claim 8 wherein the cellulose derivative is hydroxypropyl methyl cellulose.

10. An oral, controlled release coated tablet as claimed in claim 9 wherein the viscosity of 2 % aqueous dispersion of hydroxypropyl methyl cellulose ranges from about 80,000 cps to about 120,000 cps.

1 1. An oral, controlled release coated tablet as claimed in claim 10 wherein the amount of the hydroxypropyl methyl cellulose ranges from about 5 % to about 15 % by weight of the drug composition.

12. An oral, controlled release coated tablet as claimed in claim 1 wherein the swellable composition comprises a swellable excipient selected from cross linked polyvinyl pyrrolidone, cross linked carboxy methyl cellulose and sodium starch glycolate and a diluent having a wicking action for example, silicifϊed microcrystalline cellulose.

13. An oral, controlled release coated tablet as claimed in claim 1 wherein the coating comprises water insoluble polymer (s) and one or more leachable component (s).

14. An oral, controlled release coated tablet as claimed in claim 13 wherein the leachable component is selected from the group comprising wherein the leachable component is selected from the group comprising inorganic water soluble compounds, organic water soluble compounds and mixtures thereof.

15. An oral, controlled release coated tablet as claimed in claim 13 wherein the water insoluble polymer in the coating is ethyl cellulose.

16. An oral, controlled release coated tablet as claimed in claim 15 wherein coating comprises a mixture of hydrophobic plasticizer and hydrophilic plasticizers.

17. An oral, controlled release coated tablet as claimed in claim 16 wherein the hydrophobic plasticizer is selected from the group comprising dibutyl sebacate, diethyl sebacate, diethyl phthalate, vegetable and mineral oils and mixtures thereof and the hydrophilic plasticizer is selected from the group comprising triethyl citrate, triethyl acetyl citrate, triacctin, tributyl citrate, polyethylene glycol, glycerol and mixtures thereof.

18. An oral, controlled release coated tablet as claimed in claim 17 wherein the ratio of dibutyl sebacate to triethyl citrate is about 5: 1.