FORM2THE PATENTS ACT, 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10; rule 13)
1. Title of the invention. - NOVEL ORAL CONTROLLED RELEASE COMPOSITION OF CARVEDILOL
2. Applicant(s)(a) NAME :(b) NATIONALITY(c) ADDRESS : LUPIN LIMITEDAn Indian Company.159, CST Road, Kalina, Santacruz (East), Mumbai -400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
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 a novel oral controlled release composition comprising therapeutically effective amount of carvedilol or a pharmaceutically acceptable salt thereof, one or more controlled release agent(s) and other pharmaceutically acceptable excipients.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,503,067 describes a compound, which is known as carvedilol. This compound is a novel multiple action drug useful in the treatment of mild to moderate hypertension. Carvedilol is known to be both a competitive non-selective p-adrenoceptor antagonist and a vasodilator. The vasodilatory actions of carvedilol result primarily from ai-adrenoceptor blockade, whereas the β-adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension. These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug. Also, carvedilol, as a consequence of its antioxidant action in attenuating oxygen free radical-initiated lipid peroxidation, is useful in organ protection, in particular, cardioprotection. Additionally, carvedilol is useful in the treatment of congestive heart failure.
A controlled release profile from a drug dosage form is desirable in clinical use to reduce side effects and improve patient compliance. The technology used to formulate sustained release dosage forms is well documented. The entrapment of a drug in a polymer based matrix is a common approach to formulate sustained release tablets with a desirable release profiles.
It has been reported that depot drug formulations for controlled release of pharmaceutical drugs may be prepared using alginates alone (see U.S. Pat. No. 5,132,295), using combinations of alginates and polyacrylates (see U.S. Pat. No. 5,230,901) and using combinations of alginates and a pH independent gelling agent, such as, for example, hydroxypropyl methylcellulose (see U.S. Pat. No. 4,792,452). It is also known that the use of alginates alone for this purpose often presents difficulties in tableting, film coating and storage.
It also has been reported that a sustained release dosage form useful in providing once-a-day medication consists of the admixture of hydroxypropyl methylcellulose
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(viscosity of 80 to 120 cps in a 2% aqueous solution) and ethylcelluose with etodolac (see U.S. Pat. No. 4,966,768).
Matrix drug delivery system has been described in U. S. Patent No. 6,150,410. This patent discloses extended release pharmaceutical compositions of acidic pharmacological agents that have reduced dependence of the release rate upon pH and gastric residence time. The extended release compositions comprise a combination of water-swellable, hydrophilic polymer and acid soluble polymer, which is swellable above pH 5. These compositions provide an enhanced rate of release of the acidic pharmacological agent in the stomach where the pH of the gastric juices is low and diminished release rate at neutral or slightly alkaline pH of the intestines.
Further, U. S. Patent Nos. 5,695,781 and 6,083,532 disclose a three component, release rate controlling matrix composition that includes a pH dependent gelling polymer such as an alginate component, an enteric polymer and a pH independent gelling polymer.
Additionally, U. S. Patent No. 6,251,430 describes the use of ethyl cellulose or Eudragit RS or RL in combination with hydroxypropyl methylcellulose and sodium alginate to provide for a controlled release of the drug.
Despite many efforts, there still remains a need for novel controlled release pharmaceutical compositions for oral administration, from which a wide range of drugs can be released, irrespective of pH and gastric residence time.
OBJECT OF THE INVENTION
Thus an object of the invention is to provide novel controlled release pharmaceutical compositions for oral administration comprising carvedilol
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a novel oral controlled release composition comprising a therapeutically effective amount of carvedilol or a pharmaceutically acceptable salt thereof, one or more controlled release agent(s) selected from pH independent polymers, water insoluble substances and combinations thereof, and other pharmaceutically acceptable excipients.
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DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel oral controlled release composition comprising a therapeutically effective amount of carvedilol or a pharmaceutically acceptable salt thereof, one or more controlling release agent(s) selected from the group comprising pH independent polymers or water insoluble substances or combinations thereof, and other pharmaceutically acceptable excipients.
Carvedilol or pharmaceutically acceptable salts thereof can be used in the present invention, the preferred salt being carvedilol phosphate. Carvedilol or a pharmaceutically acceptable salt thereof used in the present invention may be in crystalline or amorphous or anhydrous or hydrate form thereof. These forms include but not limited to carvedilol phosphate hemihydrate (Form I) or Form A or Form B or anhydrous form or amorphous form.
By controlled release it is meant as any formulation that achieves slow release of drug over an extended period of time. It is taken to encompass sustained release, prolonged release, timed release, retarded release and extended release. An example of a controlled release system is a matrix formulation. The formulations of the present invention allow for once-a-day dosing containing 10, 20, 40, or 80 mg carvedilol phosphate.
According to the instant invention, the novel oral controlled release formulation comprises matrix controlled release agents that retards the rate of release of drug from the dosage form which include pH independent polymers or water insoluble substances or combinations thereof. Examples of pH independent polymers includes but not limited to acrylic or methacrylic polymers or co-polymers of acrylate or methacrylate monomers for example polymethacrylates marketed under the brand names of Eudragit®. These polymers include Eudragit® RS, Eudragit® RL, Eudragit® L, Eudragit® E, Eudragit® S, Eudragit® RD, particularly Eudragit® NE 30 D, Eudragit® NE 40 D and the like. Eudragit® NE 30 D is an aqueous dispersion of a neutral co-polymer consisting of polymethacrylic acid esters. These dispersions are milky-white liquids of low viscosity and have a weak aromatic odor. Films prepared from the lacquer swell in water, to which they become permeable. Thus, films produced are insoluble in water, but give pH independent drug release.
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Other pH independent polymers include a mixture of polyvinyl acetate and polyvinylpyrrolidone. This is commercially available as Kollidone® SR by BASF Aktiengesellschaft. Kollidone® SR is a spray formulated, free flowing, non-hygroscopic powder consisting of 8 parts (w/w) polyvinyl acetate and 2 parts (w/w) polyvinylpyrrolidone. Kollidone® SR has excellent flow and compression properties. Matrix formulation using Kollidone® SR show only slight swelling behaviour and the drug release was according to Higuchi's law showing a quicker release at the beginning and slower at the end, which is characteristic for an inert matrix with pores. Povidone and the active are dissolved creating pores through which further active can diffuse.
Other controlled release agents that can be used in the matrix formulation includes water insoluble substances like hydrogenated vegetable oils. These include but are not limited to hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated cottonseed oil, soybean oil, corn oil, peanut oil, palm oil, sunflower seed oil or mixtures thereof. Hydrogenated forms of the vegetable oil are preferred.
Pharmaceutically acceptable excipients used in the oral controlled release formulations of carvedilol include those known to a person ordinarily skilled in the art such as diluents, binders, and lubricants. Diluents may include but not limited to lactose, microcrystalline cellulose, dibasic calcium phosphate, mannitol, cellulose and the like. Binders may include but not limited to starches, alginates, gums, celluloses, vinyl polymers, sugars and the like. Lubricants may include but not limited to stearates such as magnesium stearate, talc, colloidal silicon dioxide and the like.
Oral controlled release compositions of carvedilol or a pharmaceutically acceptable salt thereof of the present invention may be prepared by processes like direct compression, wet granulation and dry granulation methods. The active, controlled release agent(s) together with other diluents and lubricants are blended and are either directly compressed into tablets or mini tablets or filled directly into capsules. Alternatively the active, controlled release agent(s) together with other diluents and lubricants may be dry granulated or granulated with water or controlled release agent and are either directly compressed into tablets or mini tablets or filled directly into pharmaceutically acceptable hard gelatin capsules. The size of the mini tablet varies from 1-4 mm in diameter. These mini tablets are further filled into pharmaceutically
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acceptable hard gelatin capsules using techniques well known to those ordinarily skilled in the art. One or more mini tablets are loaded into a single hard gelatin capsule to provide a unit dose. Most preferably the mini tablets provide additive amount of carvedilol without modifying the release profile. For example, by making a mini tablet containing 2.5 mg of carvedilol, capsules containing 10, 20, 40 or 80 mg of carvedilol can be formed by standard filing of capsule with 4, 8, 16 and 32 mini tablets respectively.
The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure, and the accompanying claims.
EXAMPLES Examples 1-5:

Ingredients Examples
1 2 3 4 5
Carvedilol Phosphate Hemihydrate (Form I) 5.102 g 5.102 g 5.102 g 5.102 g 5.102 g
Lactose 11.648 g 16.348 g - 16.348 g 12.348 g
Eudragit NE 40 D 5.6 g 2.8 g - 2.8 g 2-8 g
Kollidone SR - - 5.0 g - -
Dibasic Calcium Phosphate - - 14.5 g - -
Hydrogenated Vegetable Oil - - - - 4.0 g
Magnesium Stearate 0.75 g 0.75 g 0.375 g 0.75 g 0.75 g
Purified water q.s. q.s. q.s. q.s. q.s.
Brief Manufacturing Procedure:
Carvedilol phosphate is blended with diluent, lactose or dibasic calcium phosphate and granulated with controlled release agent, Eudragit NE 40 D or Hydrogenated Vegetable Oil or granulated by dissolving Kollidone SR in purified water. The granules are dried and lubricated with magnesium stearate and compressed into mini tablets. These mini tablets are then filled into pharmaceutically acceptable hard gelatin capsules.
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Example 6-8:

Ingredients Examples
6 7 8
Carvedilol Phosphate Form A 5.02 g 5.02 g 5.166g
Lactose 16.348 g 12.348 g -
EudragitNE40D 2.8 g 2.8 g -
Hydrogenated Vegetable Oil - 4.0 g -
KollidoneSR - - 10.0 g
Poly vinylpyrrol idone - - 4.0 g
Dibasic Calcium Phosphate - - 3.844 g
Magnesium Stearate 0.75 g 0-75 g 1.0 g
Purified water - - q.s.
Manufacturing Procedure: Same as examples 1-5 Example 9:

Ingredients Quantity (gnis)
Carvedilol Phosphate Amorphous 5.02
Lactose 12.348
Eudragit NE 40 D 2.8
Hydrogenated Vegetable Oil 4.0
Magnesium Stearate 0.75
Manufacturing Procedure: Same as examples 1-5 Example 10 & 11:

Ingredients Example 10 Example 11
Carvedilol Phosphate Anhydrous 5.166 g 5.166 g
Lactose 12.24 g -
Eudragit NE 40 D 2.8 g -
Kollidone SR - 10.0 g
Hydrogenated Vegetable Oil 4.0 g -
Polyvinylpyrrolidone - 4.0 g
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Dibasic Calcium Phosphate - 3.844 g
Magnesium Stearate 0.75 g l.Og
Purified water - q.s.
Manufacturing Procedure: Same as examples 1-5 Example 12 & 13:

Ingredients Example 12 Example 13
Carvedilol Phosphate Form B 5.26 g 5.26 g
Lactose 13.87 g -
EudragitNE40D 2.8 g -
Kollidone SR - 10.0 g
Hydrogenated Vegetable Oil 4.0 g -
Polyvinylpyrrolidone - 4.0 g
Dibasic Calcium Phosphate - 3.74 g
Magnesium Stearate 0.75 g l.Og
Purified water - q.s.
Manufacturing Procedure: Same as examples 1-5
DISSOLUTION
The formulations exemplified above were studied for dissolution release using USP I
apparatus, 100 rpm and using 900 ml 0.1 N hydrochloric acid for 2 hours followed by
pH 4.5 acetate buffer. Results of the dissolution profile are summarized in Table I and
II.
Table I:

Time(Hours) % Drug Release
Examples
1 2 3 4 5
1 19.7 45.0 17.6 32.2 23.3
2 21.3 56.1 31.6 41.4 27.2
3 35.5 95.9 46.9 60.6 40.4
4 43.3 49.5 70.9 52.5
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5 52.0 59.8 80.3 60.9
6 55.6 63.1 85.7 67.5
7 60.8 89.6 72.8
8 95.0 79.7
Table II:

Time (Hours) % Drug Release
Examples
6 7 9 10 11 12 13
1 39.1 15.2 14.5 9.4 26.3 12.2 26.9
2 70.0 26.4 29.8 23.4 37.6 31.3 38.9
3 108.7 53.5 48.2 42.4 55.1 56.1 57.1
4 63.3 55.6 56.0 61.7 70.4 63.9
5 70.7 62.5 65.0 65.4 82.0 69.1
6 79.5 67.3 68.7 71.0 91.8 73.2
8 72.2 83.3 78.3 96.8 80.6
10 75.9 85.5 81.2 102.2 82.3
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We claim:
1. A novel oral controlled release pharmaceutical composition comprising a
therapeutically effective amount of carvedilol or a pharmaceutically acceptable salt
thereof, one or more controlled release agent(s) selected from the group comprising
pH independent polymers or water insoluble substances or combination thereof, and
pharmaceutically acceptable excipient(s).
2. The pharmaceutical composition of claim 1, wherein the pH independent polymer comprises acrylic or methacrylic polymers or co-polymers of acrylate or methacrylate monomers or a mixture of polyvinyl acetate and polyvinylpyrrolidone or combinations thereof.
3. The pharmaceutical composition of claim 2, wherein the co-polymers of acrylate or methacrylate monomers comprises polymethacrylates.
4. The pharmaceutical composition of claim 1, wherein the water insoluble substances comprise vegetable oils such as hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated cottonseed oil, soybean oil, corn oil, peanut oil, palm oil, sunflower seed oil or mixtures thereof.
5. The pharmaceutical composition of claim 1, wherein the pharmaceutically
acceptable excipients comprise diluents, binders, and lubricants.
6. The pharmaceutical composition of claim 5, wherein the diluent comprises lactose, microcrystalline cellulose, dibasic calcium phosphate, mannitol, cellulose and mixtures thereof.
7. The pharmaceutical composition of claim 5, wherein the binder comprises starches, alginates, gums, celluloses, vinyl polymers, sugars and mixtures thereof.
8. The pharmaceutical composition of claim 5, wherein the lubricant comprises magnesium stearate, talc, colloidal silicon dioxide and mixtures thereof.
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9. The pharmaceutical composition of claim 1, wherein carvedilol or pharmaceutically
acceptable salt thereof may be in crystalline or amorphous or anhydrous or hydrate
form thereof.
10. The pharmaceutical composition of claim 1, wherein carvedilol or
pharmaceutically acceptable salt thereof is carvedilol phosphate hemihydrate (Form I)
or Form A or Form B thereof.
11. A process for preparing an oral controlled release composition of carvedilol or a pharmaceutically acceptable salt thereof comprising blending therapeutically effective amount of the active with other pharmaceutically acceptable excipient(s) and are granulated with controlled release agent comprising pH indpendent polymers or water insoluble substances or combinations thereof, or by dissolving the controlled release agent(s) in purified water and compressed into tablets or mini tablets.
12. The process for preparing an oral controlled release composition of carvedilol or a pharmaceutically acceptable salt thereof according to claim 11, wherein the mini tablets are further filled into pharmaceutically acceptable hard gelatin capsules.
Dated this 16th day of March 2007

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ABSTRACT
A novel oral controlled release pharmaceutical composition comprising a therapeutically effective amount of carvedilol or a pharmaceutically acceptable salt thereof, one or more controlled release agent(s) selected from pH independent polymers, water insoluble substances and combination thereof, and pharmaceutically acceptable excipient(s). A process for preparing an oral controlled release composition of carvedilol or a pharmaceutically acceptable salt thereof comprising blending therapeutically effective amount of the active with other pharmaceutically acceptable excipient(s) and are granulated with controlled release agent comprising pH indpendent polymers or water insoluble substances or combinations thereof, or by dissolving the controlled release agent(s) in purified water and compressed into tablets or mini tablets.
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