FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
RELEASE, MULTIPLE UNIT PHARMACEUTICAL COMPOSITIONS"


ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASfflSH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI- 400013, MAHARASHTRA, INDIA.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:


FIELD OF THE INVENTION
The present invention relates to controlled release, multiple unit pharmaceutical compositions of carvedilol or a pharmaceutically acceptable aalt thereof for oral administration, and methods of the same, which can be easily compressed into tablets or filled into capsules or sachets.
BACKGROUND OF THE INVENTION
Carvedilol phosphate is a nonselective p-adrenergic blocking agent with αl-blocking
activity. It is (2RS)-I-(9H-Carbazol-4-yloxy)-3-[[2-(2-
memoxyphenoxy)ethyl]amino]propan-2-ol phosphate salt (1:1) hemihydrate. It is a racemic mixture with the following structure:

Carvedilol phosphate is indicated for the treatment of mild-to-severe heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitor, and digitalis, to increase survival and, also, to reduce the risk of hospitalization. It is also indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of <40% (with or without symptomatic heart failure). It is also indicated for the treatment of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.
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Carvedilol phosphate is available in the United States of America as COREG CR capsules for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 8O mg carvedilol phosphate. COREG CR hard gelatin capsules are filled with carvedilol phosphate immediate-release and controlled-release mieroparticies that are drug-layered and then coated with methacrylic acid copolymers Inactive ingredients include crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone.
U.S. Patent No. 6.022,562 relates to microcapsules for the oral administration of medicinal and/or nutritional active principles (AP), which are smaller than or equal to 1000 µm in size. These microcapsules consist of particles which are coated with a coating material consisting of a mixture of a film-forming polymer derivative, a hydrophobic plasticizer, a functional agent and a nitrogen-containing polymer. These microcapsules are also characterized by their ability to remain in the small intestine for a long time (at least 5 hours) and to allow, during the residence, release and absorption of the AP.
PCT Application No. 2004056336A2 relates to controlled release multiple unit system of carvedilol for oral administration, wherein each unit includes at least one core; a first coating layer including carvedilol, surrounding at least a portion of the outer surface of the core; a second rate controlling coating layer surrounding at least a portion of the outer surface of the first coating layer and including, one or more sustained release polymers and one or more enteric polymers.
PCT Application No. 2007023325A2 relates to a controlled release pharmaceutical composition in a layered pellet form containing carvedilol. The composition contains a core containing a solid organic acid, an enteric coating layer on the core, a layer containing carvedilol and a water-soluble adhesive on the surface of the enteric coating, and a dissolution controlling layer containing a mixture of a water-soluble and an enteric polymers.
Inspite of the prior art controlled release formulations of carvedilol, there still exist need for controlled released multiple uint pharmaceutical compositions of carvedilol, wherein
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the drug coating or drug layering is robust as compared to prior art methods and wherein the composition comprising (he delayed released multiple unit pharmaceutical compositions of the invention would be bioequivalent to the commercially available controlled-release oral capsules i.e. COREG CR.
OBJECT OF THE INVENTION
It is an object of the present invention to provide controlled release multiple unit pharmaceutical compositions of caivedilol or a pharmaceutically acceptable salt tliereof for oral administration, and methods of preparing the same, which can be easily compressed into tablets or filled into capsules or sachets.
It is further the object to provide a process for preparing controlled release multiple pharmaceutical compositions of carvedilol or a phamiaceutically acceptable salt thereof of the present invention by methods which result in robust and uniform drug coating or drag layering as compared to prior art methods.
It is still further the object to provide pharmaceutical compositions comprising the controlled release multiple pharmaceutical compositions of carvedilol or a pharmaceutically acceptable salt tliereof, of the invention, which are bioequivalent to the commercially available controlled-release oral capsules i.e. COREG CR.
At least one of the preceding objects is met, in whole or in part, by the multiple pharmaceutical compositions of carvedilol or a phamiaceutically acceptable salt thereof of the present invention and the process for its preparation.
SUMMARY OF THE INVENTION
The present invention provides controlled release, multiple unit pharmaceutical compositions comprising multiple units, each unit comprising: at least one core; a first coaling layer surrounding at least a portion of the outer surface of the core comprising carvedilol or a phamiaceutically acceptable salt thereof; and a second rate delayed release
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coating layer surrounding at least a portion of the outer surface of the first coaling layer comprising one or more enteric polymers.
The present invention also provides a process for preparing controlled release, multiple unit pharmaceutical compositions comprising providing a core; coating at least a portion of the outer surface of the core with a solution comprising carvedilol or a pharmaceutieally acceptable salt thereof, and coaling at least a portion of the outer surface of the first coaling layer with a second rate delayed release coating layer comprising one or more enteric polymers.
The present invention also provides pharmaceutical compositions comprising the controlled release, multiple pharmaceutical compositions of carvedilol or a pharmaceutically acceptable salt thereof of the invention, which are bioequivalent to the commercially available controlled-release oral capsules i.e. COREG CR.
The present invention provides robust and uniform drug coating or drug layering on the core by depositing a solution comprising carvedilol or a pharmaceutically acceptable salt thereof instead of suspension or dispersions of the active used in prior art methods.
DESCRIPTION OF THE INVENTION
Before the present formulations and methods are described, it is to be understood that this invention is not limited to particular compounds, Formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Wliere a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed
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within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
The present invention relates to controlled release, multiple unit pharmaceutical compositions comprising multiple units, each unit comprising: at least one core; a first coating layer surrounding at least a portion of the outer surface of the core comprising carvedilol or a pharmaceuti colly acceptable salt thereof; and a second rate delayed release coating layer surrounding at least a portion of the outer surface of the first coating layer comprising one or more enteric polymers.
The present invention also relates to a process for preparing controlled release, multiple unit phaimaceutical compositions comprising providmg a core; coating at least a portion
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of the outer surface of the core with a solution comprising carvedilol or a
pharmaceutically acceptable salt thereof; and coating at least a portion of the outer
surface of the first coating layer with a second rate delayed release coating layer comprising one or more enteric polymers.
The present invention also further relates to pharmaceutical compostitions comprising the controlled release, multiple pharmaceutical compositions of carvedilol or a pharmaceutically acceptable salt thereof of the invention, which are bioequivalent to the commercially available controlled-release oral capsules i.e. COREG CR.
The present invention also further provides robust and uniform drug coating or drug layering on the core by depositing a solution comprising carvedilol or a pharmaceutically acceptable salt thereof instead of suspension or dispersions of the active used in prior art methods and for example in COREG CR. We have found that when the carvedilol or a pharmaceutically acceptable salt thereof and the binder are used in solution form for drug layering, it results in (a) uniform carvedilol or its pharmaceutically acceptable salt and the binder layering over the entire coating/layering operation whereas when they are in suspension form, the carvedilol or the pharmaceutically acceptable salt thereof tends to settle resulting in non-uniform coating; (b) more robust carvedilol or its pharmaceutically acceptable salt layering; (c) less batch to batch variation in the layering as compared to suspension form; and (d) less scale up issues due to the above reasons.
The term "core" or "pellet core" is used as it is generally used in the pharmaceutical industry. The core is the innermost optionally spheroid part of the pellet, on which some layers of the different composilions are placed. The core may include one or more of sugar, a non-pareil seed, microcrystalline cellulose, celphere, sand silicon dioxide, glass, plastic, polystyrene, hydroxypropyl methylcellulose and the like and mixtures thereof. The sugar may include one or more of glucose, mannitol, lactose, xylitol, dextrose, and sucrose. The core may include one or more of an insoluble material, a soluble material, and a swellable material.
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The term "carvedilol" or "carvedilol or a pharmaceutically acceptable salt thereof refers to carvedilol free base or any pharmaceutically acceptable salt of carvedilol. A particularly preferred pharmaceutically acceptable salt of carvedilol is carvedilol phosphate.
The binders that may be used in the composition of the present invention include one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacantli, sodium alginate, propylene glycol and the like and mixtures thereof.
Suitable disintegrates that may be used in the composition of the present invention include one or more of starch, crosearmellose. crospovidone, sodium starch glycolate, potassium polacrillin and the like and mixtures thereof.
Suitable plasticizers that may be used in the composition of the present invention include one or more of polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacetate, hydrogenated vegetable oil such as Lubritab, polyoxyethylene alkyl ethers such as Cremophor and the like and mixtures thereof.
The lubricants and glidants that may be used in the composition of the present invention include one or more of colloidal anhydrous silica, stearie acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax and the like and mixtures thereof.
Suitable diluents that may be used in the composition of the present invention include one or more of calcium carbonate, calcium phosphate dibasic, calcium phosphate-tribasie, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible., sugar confectioners and the like and mixtures thereof.
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Suitable stabilizers include one or more of antioxidants, buffers, acids and the like may also be used in the composition of the present invention.
Suitable coloring agents include any FDA approved colors for oral use.
The present invention uses enteric polymers to form delayed release coating layer on the drug layered core The present invention defines enteric polymers as polymers, which are able to form a gastric-acid-resistant coating layer soluble, in (lie intestinal tract. The enteric polymer may include one or more of cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate, bydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; melhacrylic acid copolymers such as Eudragit L 100-55, Eudragit L30 D-55, Eudragit L 100, and Eudragit S 100, and the like and mixtures thereof.
The carvedilol or a pharniaceutically acceptable salt thereof is applied as an aqueous solution of the drug in water or organic solvent, or mixtures thereof. We have found that robust and uniform drug layering on the core is obtained if a solution comprising carvedilol or a phannaceiitically acceptable salt thereof is deposited on the core instead of suspension or dispersions of the drug used in prior art methods for application over the core. The carvedilol or a pharniaceutically acceptable salt thereof can be applied over me inert cores as solution of the drug using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor: dip coaling and the like. The carvedilol or its pharniaceutically acceptable salt layer may be applied by placing the core particles in a fluid bed apparatus, e.g.. a fluid bed bottom spray coater, such as, the Wurster coating apparatus (Pharmaceutical Pelletization Tecluiology, (1989) pp. 50-54, ed. Isaac Ghebre-Sellassie, Marcel Dekker, Inc , New York and Basel). A solution of the carvedilol or a pharniaceutically acceptable salt thereof is sprayed on the fluidizing bed of cores until the desired amount of drug loading or layering is achieved. The layering solution of carvedilol or a pharmaceurically acceptable salt thereof is fanned by dissolving the active in distilled water or other pharniaceutically acceptable liquid such as a volatile organic solvent. Antiadherents and
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binders such as hydroxypropyl methyl cellouIose and other excipients or ingredients as is desirable or appropriate may be added to the solution.
The carvedilol layered cores may then be coated with a delayed release coating comprising enteric polymer or a mixture of enetric polymers. The delayed release layer coating may be applied as suspension of the enteric polymers using any conventional teclinique known in the prior art such as spray coating in a conventional coaling pan or fluidized bed processor; dip coaling and the like.
The controlled release multiple pharmaceutical compositions of carvedilol or a pharmaceulieally acceptable salt (liereof of the invention, may be provided in a pharmaceutical composition. In an embodiment, the pharmaceutical composition comprising the controlled release multiple pharmaceutical compositions of carvedilol or a pharmaceulically acceptable salt thereof of the invention is bioequivalent to the commercially available controlled-release oral capsules i.e. COREG CR. In an embodiment, the controlled release multiple pharmaceutical compositions of carvedilol or a pharmaceutically acceptable salt thereof of the invention are filled in capsules, in anotlier embodiment, the controlled release multiple pharmaceutical compositions of carvedilol or a pharmaceutically acceptable salt thereof of the invention may be converted into tablets by processes known in the relevant art, e.g., comminuting, mixing, granulating, sizing, filling, molding, spraying, immersing, coating, compressing, etc.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
EXAMPLE 1
The pharmaceutical composition comprising the controlled release multiple unit pharmaceutical compositions of carvedilol or a pharmaceulically acceptable salt thereof of the invention may be prepared as given in Table 1.
Table 1
S.NO. Ingredients Qfy %w/w Category
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(mg)/Capsuie Immediate Release pellets (IR Pellets)

1
2
3 4

Celphere CP 305 Carvedilol Phosphate
Hydroxypropyl
methylcellulose (HPMC)
Water (Purified))

35 10
qs

core

74.48 21.27
4.25

Diluents Active
Binder
Solvent

Delayed Release pellets (DR I Pellets)
core

1 Celsphere CP 305 45 35.45% of core Diluents
2 Carvedilol 30 23.62% of Active

Phosphate
core
Hydroxypropyl 15.74% of Binder
3 methylcellulose (HPMC) 20 core
4 Potassium 30 23.62% of Disintegrant

polacrillin
core
5 Cremophore RH 2 1.57% of core Plasticizer

40 £*
6 Water (Purified)) qs Coating Solvent
1 Eudrgit LI 00-55 7.62 60% of coat Enteric coaling
2 3 Lubritab
Isopropyl
alcohol 5.08 qs 40% of coat Plasticizer Solvent
Delayed Release pellets (DR II Pellets)

core
Celsphere CP 150 69.12% of Diluents
305 core
Carvedilol 40 18.43% of Active
Phosphate
core
Hydroxypropyl 5.52% of core Binder
methy cellulose 12
(HPMC)
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4
5 6
Potassium polacrilin
Cremophore RH 40
Water (Purified))
1 EudrgitLlOO-55
Eudragit 1OO
3 4
Lubritab
Isopropyl alcohol

12
5.52% of core

3 1.38% of core
qs
Coating
7.59 34.97% of coat
5.42 24.97% of coat
8.69 40.06% of coat
qs

Disintegrant
Plasticizer
Solvent
Enteric coaling
Enteric coating
Plasticizer
Solvent

Immediate Release Pellets (IR Pellets):
Purified water was taken in quantity sufficient to dissolve carvedilol phosphate. To
solution, HPMC was added under stirring to dissolve. Drug layering of the prep;
solution was carried out on Celphere CP 305 till desire weight gain.
Delayed Release Pellets (DR I)
Purified water was taken in quantity sufficient to dissolve can'edilol phosphate. To this
solution, HPMC was added under stirring to dissolve. Polacrilin potassium and
Cremophore RH 40 were added to the prepared solution and stirred for 30 minutes. Drug
layering was carried out on Celphere CP 305 using the prepared dispersion till desired
weight gain.
Coating:
Eudragit L 100-55 was dispensed in isopropyl alcohol, Lubrilab was added to this and
stirred till uniform. The suspension was then passed through 200 ASTM mesh and used
to coat the pellet to desired weight gain.
Delayed Release Pellets (DR II)
Purified water was taken in quantity sufficient to dissolve carvedilol phosphate. To this
solution, HPMC was added under stirring to dissolve. Polacrilin potassium and
Cremophore RH 40 were added to the prepared solution .and stirred for 30 minutes. Drug
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layering was carried out on Celphere CP 305 using the prepared dispersion rill desired weight gain.
Coating:
Eudragit L 100-55 and and Eudragit S 100 were dispensed in isopropyl alcohol, Lubritab was added to this and stirred till uniform. The suspension was then passed through 200# ASTM mesh and used to coat the pellet to desired weight gain.
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications witliout departing from the spirit of or exceeding (lie scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
Dated this 29th day of May 2008

To:
The Controller of Patents, Patent Office, Mumbai 400037
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