Extended release dosage forms of metoprolol

This application is a continuation of U.S. application Ser. No. 12/225,746, filed Apr. 13, 2009, now U.S. Pat. No. 8,815,285, which entered the National Phase of Serial No. PCT/IB2007/000776, filed Mar. 28, 2007, which claims benefit of an Indian Patent Application No. 1600/MUM/2006, filed Sep. 29, 2006; an Indian Patent Application No. 453/MUM/2006, filed Mar. 28, 2006; and an Indian Patent Application No. 452/MUM/2006, filed Mar. 28, 2006. The entire disclosure of these prior applications are hereby incorporated by reference.

Not Applicable.

Not Applicable.

The present invention relates to extended release dosage forms of metoprolol or salts thereof comprising a water insoluble and non-swellable inert core and one or more pharmaceutically acceptable excipients. The invention also relates to processes for the preparation of an inert core and extended release dosage forms.

Metoprolol is a beta1-selective (cardioselective) adrenoceptor blocking agent. It is commercially available in two salt forms; one of them is tartrate salt available as Lopressor tablets and the other is succinate salt (Formula I) available as Toprol-XL tablets. Metoprolol is chemically, (±) 1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol. Metoprolol succinate is indicated in the treatment of hypertension, angina pectoris and heart failure.

U.S. Pat. Nos. 4,927,640 and 4,957,745 disclose a controlled release preparation containing a number of beads comprising insoluble cores coated with metoprolol. The beads have a high content of metoprolol in the range of 95-100% w/w of the soluble part of the bead. Insoluble cores, such as glass and silicon dioxide are used.

U.S. Pat. No. 5,001,161 discloses a pharmaceutical composition comprising metoprolol succinate together with a sustained release pharmaceutically acceptable carrier.

U.S. Patent Publication 20030185887 discloses a controlled or sustained release dosage formulation of propranolol where the inert core is coated with a solution of propranolol, water insoluble binder and filler. The active core so produced is further coated with a release-controlling layer.

U.S. Patent Publication 20050008701 discloses a controlled release pellet comprising water-soluble or water swellable inert core and a drug layer applied to it, along with a controlled release coating surrounding the drug layer

International (PCT) Publication WO2005084636 discloses an oral controlled-release pharmaceutical composition of metoprolol succinate comprising a water-soluble, water swellable or water-insoluble inert core; one or more drug layers comprising metoprolol and one or more polymeric coatings surrounding the one or more drug layers. The water-soluble inert core comprises sugar sphere or salt, water insoluble inert core comprises silicon dioxide, small particles of glass, plastic resin particles or mixtures thereof and water swellable inert core comprises hydroxypropyl methylcellulose, microcrystalline cellulose, starch or mixture thereof.

Several other controlled release/extended release pharmaceutical compositions are known for example, in U.S. Pat. Nos. 5,399,362; 5,399,358; 5,707,656; 5,709,882; and 4,871,549; U.S. Application Nos. 20020177579; 20050266078; 20060003007; and 20040228915.

In one general aspect there is provided an inert core for preparation of a solid oral dosage form wherein, the core comprises microcrystalline cellulose spheres coated with one or more water insoluble pharmaceutically acceptable polymers, the inert core further comprise one or more coatings with one or more pharmaceutically active ingredients and other pharmaceutically acceptable excipients, which is optionally coated with one or more release controlling polymers.

The phrase “inert core,” as used herein, includes core that is water insoluble and non-swellable.

The phrase “solid oral dosage form,” as used herein, refers to tablets, capsules, pellets, sachets, and the like.

The phrase “insoluble,” as used herein, refers to inert core, which does not dissolve in water.

The pharmaceutically active ingredients comprise one or more of lansoprazole, pantoprazole, metoprolol, propranolol, diltiazem, tamsulosin, diclofenac, itraconazole, venlafaxine, tolterodine and pharmaceutically acceptable salts or derivatives thereof.

The pharmaceutically acceptable polymer comprises one or more of acrylic polymers or copolymers, ethylcellulose and like.

The release controlling polymers comprises one or more of cellulose ethers and acrylic acid polymers.

Embodiments of the dosage form comprises one or more of the following features. For example, the dosage form comprises other pharmaceutically acceptable excipients. The other excipients comprise one or more of fillers, binders, superdisintegrants, disintegrants, lubricants, glidants, plasticizers, anti-adherents, aqueous or non-aqueous solvents, cushioning agents, polymers and the like.

In another general aspect there is provided an extended release dosage form of metoprolol or salts thereof comprising an inert core comprising microcrystalline cellulose spheres coated with a polymer optionally having other pharmaceutically acceptable excipients, the inert core is further coated with drug comprising metoprolol or salt thereof optionally having other pharmaceutically acceptable excipients, the drug coat is further coated with one or more pharmaceutically acceptable rate-controlling polymer to give a desired release profile.

The pharmaceutically acceptable rate-controlling polymer comprises one or more of cellulose ethers and acrylic acid polymers.

Embodiments of the dosage form comprise one or more of the following features. For example, the dosage form comprises other pharmaceutically acceptable excipients. The other excipients comprises one or more of fillers, binders, superdisintegrants, disintegrants, lubricants, glidants, plasticizers, anti-adherents, aqueous or non-aqueous solvents, cushioning agents, polymers and the like.

In another general aspect there is provided a dosage form comprising an inert core comprising one or more pharmaceutically active ingredients and one or more pharmaceutically acceptable excipients or an inert core coated with one or more pharmaceutically active ingredients and one or more pharmaceutically acceptable excipients, which is optionally further coated with one or more pharmaceutically acceptable release controlling polymers and then coated with colloidal silicon dioxide.

Colloidal silicon dioxide minimizes crushing of pellets during tablet compression. Thus present invention provides a method for minimizing crushing of pellets.

The pharmaceutically active ingredients comprise one or more of lansoprazole, pantoprazole, metoprolol, propranolol, diltiazem, tamsulosin, diclofenac, itraconazole, venlafaxine, tolterodine and pharmaceutically acceptable salts or derivatives thereof.

The pharmaceutically acceptable release controlling polymers comprises one or more of cellulose ethers and acrylic acid polymers.

Embodiments of the dosage form comprises one or more of the following features. For example, the dosage form comprises one or more pharmaceutically acceptable excipients. The excipients comprises one or more of fillers, binders, superdisintegrants, disintegrants, lubricants, glidants, plasticizers, anti-adherents, aqueous or non-aqueous solvents, cushioning agents, polymers and the like.

In another general aspect there is provided an extended release dosage form of metoprolol or salt thereof comprising an inert core comprising metoprolol or salt thereof and one or more pharmaceutically acceptable excipients or an inert core coated with metoprolol or salt thereof and one or more pharmaceutically acceptable excipients, which is optionally further coated with one or more pharmaceutically acceptable release controlling polymers to impart desired release profile and then coated with colloidal silicon dioxide.

Colloidal silicon dioxide minimizes crushing of pellets during tablet compression. Thus present invention provides a method for minimizing crushing of pellets.

The pharmaceutically acceptable release controlling polymers comprises one or more of cellulose ethers and acrylic acid polymers.

Embodiments of the dosage form comprises one or more of the following features. For example, the dosage form comprises one or more pharmaceutically acceptable excipients. The excipients comprises one or more of fillers, binders, superdisintegrants, disintegrants, lubricants, glidants, plasticizers, anti-adherents, aqueous or non-aqueous solvents, cushioning agents, polymers and the like.

In another general aspect there is provided an inert core for preparation of solid oral dosage form, wherein the inert core is insoluble and non-swellable and comprises microcrystalline cellulose spheres coated with one or more pharmaceutically acceptable polymers in admixture with one or more pharmaceutically acceptable excipients.

The present invention provides a water insoluble and non-swellable inert core.

The phrase “insoluble,” as used herein, refers to inert core, which does not dissolve in water.

The phrase “non-swellable,” as used herein, refers to inert core having 20% or less swelling after 24 hours.

The pharmaceutically acceptable polymer comprises one or more of acrylic polymers or copolymers, ethylcellulose and like.

Embodiments of the dosage form comprises one or more of the following features. For example, the dosage form comprises one or more pharmaceutically acceptable excipients. The excipients comprises one or more of fillers, binders, superdisintegrants, disintegrants, lubricants, glidants, plasticizers, anti-adherents, aqueous or non-aqueous solvents, cushioning agents, polymers and the like.

In another general aspect there is provided an extended release dosage form of metoprolol or salt thereof comprising plurality of beads comprising

a) water insoluble and water non-swellable inert core; b) one or more drug layers comprising metoprolol or salt thereof in admixture with pharmaceutically acceptable excipients; c) one or more pharmaceutically acceptable rate controlling polymer surrounding one or more drug layers; and d) optionally one or more non functional coatings surrounding the one or more polymeric coatings

The phrase “insoluble,” as used herein, refers to inert core, which does not dissolve in water.

The phrase “non-swellable,” as used herein, refers to inert core having 20% or less swelling after 24 hours.

The pharmaceutically acceptable rate controlling polymers comprises one or more of cellulose ethers and acrylic acid polymers.

Embodiments of the dosage form comprises one or more of the following features. For example, the dosage form comprises one or more pharmaceutically acceptable excipients. The excipients comprises one or more of fillers, binders, superdisintegrants, disintegrants, lubricants, glidants, plasticizers, anti-adherents, aqueous or non-aqueous solvents, cushioning agents, polymers and the like.

The non functional coatings comprise one or more of polyethylene glycols and colloidal silicon dioxide.

In another general aspect there is provided an extended release dosage form of metoprolol or salt thereof comprising plurality of beads wherein the dosage form comprise water insoluble and water non-swellable inert core, the inert core is further coated with metoprolol or salt thereof which is further coated with one or more pharmaceutically acceptable rate-controlling polymer.

The phrase “insoluble,” as used herein, refers to inert core, which does not dissolve in water.

The phrase “non-swellable,” as used herein, refers to inert core having 20% or less swelling after 24 hours.

The pharmaceutically acceptable rate controlling polymers comprises one or more of cellulose ethers and acrylic acid polymers.

Embodiments of the dosage form comprises one or more of the following features. For example, the dosage form comprises one or more pharmaceutically acceptable excipients. The excipients comprises one or more of fillers, binders, superdisintegrants, disintegrants, lubricants, glidants, plasticizers, anti-adherents, aqueous or non-aqueous solvents, cushioning agents, polymers and the like.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

The inventors have found that microcrystalline cellulose pellets (Celphere CP 203) that is water swellable, when coated with water insoluble polymer ethylcellulose (Ethocel) layer in admixture with one or more pharmaceutically acceptable excipients comprising plasticizer and solvent can be used as an inert core. The formed inert core was found to be water insoluble and non-swellable. The inert core further coated with one or more drug layers, further coated with one or more release controlling layers to provide controlled release, sustained release or extended release dosage forms. The inventors have also found that an extended release pellets of metoprolol or salt thereof when coated with colloidal silicon dioxide (Aerosil 200) crushing of pellets during tablet compression was minimized.

The inert core also called as seal coat can be used to prepare immediate release, extended release, controlled release or sustained release dosage forms of various categories of drugs. Microcrystalline cellulose spheres are water swellable however the present invention provides a non-swellable inert core that is prepared by coating microcrystalline cellulose spheres with ethylcellulose in admixture with plasticizer, anti-adherent and suitable solvent. Also the inert core of present invention is water insoluble. The inert core is prepared by dissolving Ethocel and triacetin in suitable solvent and then Celphere CP 203 is coated with it in fluid bed processor at optimum parameters.

The extended release dosage form comprises metoprolol as an active ingredient, which is present in the form of metoprolol succinate. The extended release dosage form of metoprolol succinate is prepared using a water insoluble and water non-swellable inert core wherein an inert core comprises of microcrystalline cellulose spheres coated with water insoluble polymer ethylcellulose in admixture with one or more of plasticizer, anti-adherent and solvent. The inert core is further coated with a drug solution or suspension comprising drug, opadry and suitable solvent, in fluid bed processor at optimum parameters. The drug layer is further coated in fluid bed processor at optimized parameters with an extended release coat wherein one or more pharmaceutically acceptable rate controlling polymers are dissolved in a suitable solvent. The coated pellets are further blended in suitable blender with one or more pharmaceutically acceptable excipients comprising one or more of fillers, superdisintegrants, lubricants, glidants and the like. The pellets are further compressed to form tablets using suitable tooling.

The extended release coated pellets are further coated with Aerosil coat. The Aerosil coat is prepared by mixing Opadry and colloidal silicon dioxide (Aerosil 200) in suitable solvent and then coating the extended release coated pellets with it in fluid bed processor at optimum parameters. The Aerosil coated pellets are further blended in suitable blender with one or more pharmaceutically acceptable excipients comprising one or more of fillers, superdisintegrants, lubricants, glidants and the like. The pellets are further compressed to form tablets using suitable tooling.

The extended release coated pellets is further coated with one or more non-functional coatings. The non-functional coating comprises one or more of Polyethylene glycol (PEG) and colloidal silicon dioxide. The PEG coated pellets are further blended in suitable blender with one or more pharmaceutically acceptable excipients comprising one or more of fillers, superdisintegrants, lubricants, glidants, cushioning agents and the like. The obtained blend can be optionally compressed to form tablet using suitable tooling or filled into capsule.

The pharmaceutically acceptable rate controlling polymers comprises one or more of cellulose ethers, acrylic acid polymers and mixtures, thereof. Suitable cellulose ethers comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers. Suitable acrylic acid polymers comprises one or more of polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name Carbopol.

The pharmaceutically acceptable excipients comprises one or more of fillers, binders, superdisintegrants, disintegrants, lubricants, glidants, plasticizers, anti-adherents, aqueous or non-aqueous solvents, cushioning agents, polymers and the like.

The fillers comprise one or more of Avicel PH 101, Avicel PH 102, lactose, and dicalcium phosphate.

The binder comprise one or more of hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, ethylcellulose or mixtures thereof.

The Superdisintegrant comprise one or more of croscarmellose sodium, crospovidone and sodium starch glycolate.

The Disintegrant comprise one or more of croscarmellose sodium, crospovidone and sodium starch glycolate.

The Lubricants comprise one or more of magnesium stearate, calcium stearate, and sodium benzoate.

The glidants comprise be one or more of colloidal silicon dioxide and talc.

The plasticizers comprise one or more of diethyl phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, polyethylene glycol and the like.

The anti-adherent comprise one or more of talc.

The solvents comprise one or more of dichloromethane, acetone, ethanol, methanol, isopropyl alcohol, water or mixture thereof.

The Cushioning agent comprise one or more of PEG, colloidal silicon dioxide and the like.

The Non-functional coating comprises one or more of Polyethylene glycols (PEGs), colloidal silicon dioxide and the like.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.