WO2010089760A2

WO2010089760A2 - Controlled release, multiple unit pharmaceutical compositions

Info

Publication number: WO2010089760A2
Application number: PCT/IN2009/000310
Authority: WO
Inventors: Rampal Ashok; V. Sathyanarayana; Agarwala Udit; Kumar Singh Dinesh; Tallam Satyanarayan
Original assignee: Alkem Laboratories Ltd.
Priority date: 2008-05-29
Filing date: 2009-05-29
Publication date: 2010-08-12
Also published as: WO2010089760A3

Abstract

The present invention relates to a controlled release, multiple unit pharmaceutical composition comprising a plurality of the same type of controlled release units, wherein each unit comprises of a core, a first coating layer surrounding the outer surface of the said core, wherein the coating layer comprises carvedilol or a pharmaceutically acceptable salt thereof; a second coating layer surrounding the outer surface of the first coating layer comprising one or more enteric polymers; and optionally, one or more additional coating layer(s) which are the first coating layer and/or second coating layer surrounding the outer surface of the second coating layer.

Description

CONTROLLED RELEASE, MULTIPLE UNIT PHARMACEUTICAL

COMPOSITIONS

FIELD OF THE INVENTION

The present Invention relates to controlled release, multiple unit pharmaceutical compositions of carvedilol or a pharmaceutically acceptable salt thereof for oral administration and processes for preparing thereof.

BACKGROUND OF THE INVENTION

Carvedilol phosphate is a nonselective β-adrenergic blocking agent with αl-bloeMng activity. It is (2RS)-l-(9H-Carbazol-4-yloxy)-3-[[2-(2- methoxyphenoxy)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 cardiomyopathy 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 thiazϊde-type diuretics.

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 80 mg carvedilol phosphate. COREG CR hard gelatin capsules are filled with carvedilol phosphate immediate-release and controlled-release microparticles that are drag-layered and then coated with methacrylic acid copolymers. Inactive ingredients include crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystallϊne 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.

U.S. Patent Application No. 20050175695 Al relates to a controlled-release microparticle composition of carvedilol free base or a carvedilol, salt, solvate, or anhydrous form thereof. This patent application discloses a tri-component, controlled-release microparticle containing dosage form comprising a first rapidly releasing microparticle population, a first controlled release microparticle population and a second controlled release microparticle population. This rapidly releasing microparticle population consists of at least one nitrogen containing polymer and a plasticizer or other pharmaceutically acceptable excipients and controlled release microparticle population additionally comprises at least one release controlling coating layer(s).

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.

In spite of the prior art controlled release formulations of carvedilol, there still exists a need for controlled released, multiple unit pharmaceutical compositions of carvedilol, wherein the pharmaceutical composition is a unicomponent system containing plurality of the same type of controlled release units so as to provide an economical pharmaceutical composition with simplified process of preparation. Also there remains a need for prior art formulations of carvedilol phosphate, wherein the drug coating or drug layering is easier to apply & robust as compared to prior art methods, which also provide increased solubility which leads to improved bioavailability when the drug is administered to a patient.

We have now found a controlled release, multiple unit pharmaceutical composition to address aforementioned needs by providing a plurality of the same type of controlled release units, wherein such controlled release units, in one aspect, comprise coating of a solution of carvedilol or a pharmaceutically acceptable salt thereof.

OBJECT OF THE INVENTION

It is an object of the present invention to provide controlled release, multiple unit pharmaceutical compositions of carvedilol or a pharmaceutically acceptable salt thereof for oral administration, and methods of preparing the same, which can be easily compressed into tablets or filled into capsules or sachets.

It is an object of the present invention to provide controlled release, multiple unit pharmaceutical compositions of carvedϊlol or a pharmaceutically acceptable salt thereof comprising a plurality of the same type of controlled release units.

It is yet another object to provide a process for preparing controlled release, multiple unit pharmaceutical compositions of carvediloϊ or a pharmaceutically acceptable salt thereof of the present invention by methods which result ϊn robust and uniform drug coating or drug layering as compared to prior art methods.

At least one of the preceding objects is met, in whole or in part, by the controlled release, multiple unit pharmaceutical compositions of carvedilol or a pharmaceutically acceptable salt thereof of the present invention and the process for its preparation.

SUMMARY OF THE INVENTION

The present invention provides a controlled release, multiple unit pharmaceutical composition comprising a plurality of the same type of controlled release units, wherein each unit comprises,

(a) a core;

(b) a first coating layer surrounding the outer surface of the core (a), wherein the coating layer comprises carvedilol or a pharmaceutically acceptable salt thereof; (c) a second coating layer surrounding the outer surface of the first coating layer (b) comprising one or more enteric polymers; and (d) optionally, one or more additional coating layer(s) which are the first coating layer

(b) and/or second coating layer (c) surrounding the outer surface of the second coating layer (c). The present invention also provides a process for preparing a controlled release, multiple unit pharmaceutical composition comprising a plurality of the same type of controlled release units comprising (a) providing a core; (b) coating the outer surface of the core (a) with a solution or a suspension comprising carvedilol or a pharmaceutically acceptable salt thereof;

(c) coating the outer surface of the first coating layer (b) with a second coating layer comprising one or more enteric polymers; and

(d) optionally, coating the outer surface of the second coaling layer (c) with one or more additional coating layer(s) which are the first coating layer (b) and/or second coating layer (c) surrounding the outer surface of the second coating layer (c) to form individual units;

(e) combining a plurality of the individual units in a dosage form.

The present invention may be summarized as given below:

A. A controlled release, multiple unit pharmaceutical composition comprising a plurality of the same type of controlled release units, wherein each unit comprises,

(a) a core; (b) a first coating layer surrounding the outer surface of the core (a), wherein the coating layer comprises carvedilol or a pharmaceutically acceptable salt thereof;

(c) a second coating layer surrounding the outer surface of the first coating layer (b) comprising one or more enteric polymers; and

(d) optionally;, one or more additional coating layer(s) which are the first coating layer (b) and/or second coating layer (c) surrounding the outer surface of the second coating layer (c).

B. The controlled release, multiple unit pharmaceutical composition of A, wherein the first coating layer (b) comprises depositing a suspension of carvedilol or a pharmaceutically acceptable salt thereof. C. The controlled release, multiple unit pharmaceutical composition of A, wherein the first coating layer (b) comprises depositing a solution of carvedilol or a pharmaceutically acceptable salt thereof.

D, The controlled release, multiple unit pharmaceutical composition of C, wherein the first coating layer (b) comprising depositing the solution of carvedilol or a pharmaceutically acceptable salt thereof, is prepared in a methanol-methylene chloride solvent system.

E. The controlled release, multiple unit pharmaceutical composition of D, wherein the carvedilol or a pharmaceutically acceptable salt thereof in the first coating layer (b) is in amorphous form.

F. The controlled release, multiple unit pharmaceutical composition of A₅ wherein the core (a) includes one or more of sugar, a non-pareil seed, microcrystalline cellulose, celphere, sand silicon dioxide, glass, plastic, polystyrene, hydroxypropyt methylcellulose and the like and mixtures thereof.

G. The controlled release, multiple unit pharmaceutical composition of A, wherein the second coating layer (c) comprises one or more enteric polymers selected from cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcelhilose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; methacrylic acid copolymers such as Eudragit L 100-55, Eudragit L30D-55, Eudragit L 100, Eudragit L 12,5, Εudragit S 100, Eudragit S 12,5, and Eudragit FS 30 D and the like and mixtures thereof.

H. The controlled release, multiple unit pharmaceutical composition of G, wherein the enteric polymers are used in amounts ranging from about 2 % w/w to about 25 % w/w.

I. The controlled release, multiple unit pharmaceutical composition of A, wherein the first coating layer (b), the second coating layer (c) and the optional one or more additional coaling layer(s) (d) include one or more pharmaceutically acceptable excipients.

J. The controlled release, multiple unit pharmaceutical composition of I, wherein the pharmaceutically acceptable excϊpϊents include binders, diluents, disintegraπts₅ lubricants, glidants, plasticϊzers, stabilizers, and coloring agents.

K, The controlled release, multiple unit pharmaceutical composition of A, wherein the pharmaceutical composition comprises a tablet, a capsule, a sachet and the like.

L. The controlled release, multiple unit pharmaceutical composition of K, wherein the pharmaceutical composition is a capsule.

M. A process for preparing a controlled release, multiple unit pharmaceutical composition comprising a plurality of the same type of controlled release units comprising

(a) providing a core;

(b) coating the outer surface of the core (a) with a solution or a suspension comprising carvedilol or a pharmaceutically acceptable salt thereof; (c) coating the outer surface of the first coating layer (b) with a second coating layer comprising one or more enteric polymers; and

(d) optionally, coating the outer surface of the second coating layer (c) with one or more additional coating layer(s) which are the first coating layer (b) and/or second coating layer (c) surrounding the outer surface of the second coating layer (c) to form individual units;

(e) combining a plurality of the individual units in a dosage form.

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.

Where 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 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.

(a) a core;

(b) a first coating layer surrounding the outer surface of the core (a), wherein the coating layer comprises carvedilol or a pharmaceutically acceptable salt thereof; (c) a second coating layer surrounding the outer surface of the first coating layer (b) comprising one or more enteric polymers; and

(d) optionally, one or more additional coating layer(s) which are the first coating layer (b) and/or second coating layer (c) surrounding the outer surface of the second coating layer (c).

The present invention provides a process for preparing a controlled release, multiple unit pharmaceutical composition comprising a plurality of the same type of controlled release units comprising,

(a) providing a core; (b) coating the outer surface of the core (a) with a solution or a suspension comprising carvedilol or a pharmaceutically acceptable salt thereof;

(d) optionally, coating the outer surface of the second coating layer (c) with one or more additional coating ϊayer(s) which are the first coating layer (b) and/or second coating layer (c) surrounding the outer surface of the second coating layer (c) to form individual units;

(e) combining a plurality of the individual units in a dosage form.

In general, the present invention provides a controlled release, multiple unit pharmaceutical composition comprising a unicomponent system i.e. having plurality of the same type of controlled release units, wherein each unit comprises, (a) a core; (b) a first coating layer surrounding the outer surface of the core (a), wherein the coating layer comprises carvedilol or a pharmaceutically acceptable salt thereof; (c) a second coating layer surrounding the outer surface of the first coating layer (b) comprising one or more enteric polymers; and (d) optionally, one or more additional coating layer(s) which are the first coating layer (b) and/or second coating layer (c) surrounding the outer surface of the second coating layer (c).

In one embodiment of the present invention, the first coating layer comprises depositing a suspension of carvedilol or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the first coating layer comprises depositing a solution of carvedilol or a pharmaceutically acceptable salt thereof.

In yet another embodiment of the present invention, the first coating layer comprises depositing a solution of carvedilol or a pharmaceutically acceptable salt thereof, wherein the solution of carvedilol or a pharmaceutically acceptable salt thereof is prepared by dispersing carvedilol in a mixture of methanol-methylene chloride solvent system with continuous stirring. This results in a pharmaceutical composition with a coating comprising amorphous form of carvedilol or a pharmaceutically acceptable salt thereof which exhibits increased solubility.

The present invention also further provides robust and uniform drag coating or drug layering on the core by depositing a solution comprising carvedilol or a pharmaceutically acceptable salt thereof. We have found that when the solution of carvedilol or a pharmaceutically acceptable salt thereof is used for drug layering in the present invention, it results in (a) uniform carvedilol or its pharmaceutically acceptable salt layering over the entire coating/layering operation; (b) more robust carvedilol or its pharmaceutically acceptable salt layering; {c) less batch to batch variation in the layering; 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 compositions are placed. The core may include one or more of sugar, a non-pareil seed, niicrocrystalline 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.

The term "carvediloi" or "carvedilol or a pharmaceutically acceptable salt thereof refers to carvedϊlol free base or any pharmaceutically acceptable salt of carvedilol, A particularly preferred pharmaceutically acceptable salt of carvedilol is carvedilol phosphate. The controlled release pharmaceutical composition of the present invention may include carvedilol phosphate in amounts ranging from about 10 % w/w to about 50 % w/w, preferably from about 15 % w/w to about 30 % w/w of the composition.

The controlled release, multiple unit pharmaceutical composition of the present invention comprises a plurality of the same type of controlled release units, wherein each unit comprises, first coating layer (b) surrounding at least a portion of the outer surface of the core, wherein the coating layer comprises carvedilol or a pharmaceutically acceptable salt thereof. The first coating layer may comprise either depositing a suspension or a solution of carvedilol or a pharmaceutically acceptable salt thereof. It is particularly preferred to use a solution of carvedilol or a pharmaceutically acceptable salt thereof. It is further preferred that the solution of carvedilol or a pharmaceutically acceptable salt thereof is prepared in a methanol-methylene chloride solvent system. Coating the core with the solution of carvedilol or a pharmaceutically acceptable salt thereof prepared in such a solvent system provides amorphous form of carvediloi or a pharmaceutically acceptable salt thereof.

The present invention uses enteric polymers to form the second coating layer (c) on the drug layered core. The enteric polymers are generally polymers which are able to form a gastnc-acid-resistant coating layer soluble m the intestinal tract. However, the present invention uses these enteric polymers in lower concentrations so as to provide controlled release of the earvedilol or a pharmaceutically acceptable salt thereof instead of delaying its release. The controlled release polymer may include one or more of cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; methacrylic acid copolymers such as Eudragit L 100-55, Eudragit L30 D-55, Eudragit L 100, Eudragit L 12,5, Eudragit S 100, Eudragit S 12,5, and Eudragit FS 30 D and the like and mixtures thereof. The enteric polymers may be present in the composition of the present invention in an amount ranging from about 2 % w/w to about 25 % w/w of the composition.

Each unit of the controlled release, multiple unit pharmaceutical composition of the present invention may optionally include one or more coating layer(s) (d) coated on the second coating layer (c). The one or more coating layer(s) may comprise the first coating layer of either depositing a suspension or a solution of caryedilol or a pharmaceutically acceptable salt thereof and/or the second coating layer comprising enteric polymers. In one embodiment, the present invention provides each unit of the controlled release, multiple unit pharmaceutical composition comprising a core, a first coating layer of carvedilol or a pharmaceutically acceptable salt thereof, a second coating layer of enteric polymers coating and a further coating layer of carvedilol or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides each unit of the controlled release, multiple unit pharmaceutical composition comprising a core, a first coating layer of carvedilol or a pharmaceutically acceptable salt thereof, a second coating layer of enteric polymers, a further coating layer of carvedilol or a pharmaceutically acceptable salt thereof, a still further coating layer of enteric polymers and a last coating layer of carvedilol or a pharmaceutically acceptable salt thereof

The controlled release, multiple unit pharmaceutical composition comprising plurality of the same type of controlled release units of the present invention may include one or more pharmaceutically acceptable excipients such as diluents, binders, disintegrates, lubricants, glidants, plasticizers, stabilizers, and coloring agents in the first coating layer (b), the second coating ϊayer (c) and the optional coating layer(s) (d).

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-tribasic, calcium sulfate, microcrystalline cellulose, siHcϊfied mϊcrocrystalline 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. The diluents may be present in the composition of the present invention in an amount ranging from about 5 % w/w to about

75 % w/w of the composition.

The binders that may be used in the composition of the present invention include one or more of methyl cellulose, hydroxypropyl cellulose, Iiydroxypropyl methyleellulose, polyvinylpyrrolidone, gelatin, gum arabic, «thyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol and the like and mixtures thereof. The binders may be present in the composition of the present invention in an amount ranging from about 1 % w/w to about 10 % w/w of the composition.

Suitable disintegrants that may be used in the composition of the present invention include one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, potassium polacrillm and the like and mixtures thereof. The disintegrants may be present in the composition of the present invention in an amount ranging from about 1 % w/w to about 25 % w/w of the composition.

The lubricants and gϊidants that may be used in the composition of the present invention include one or more of colloidal anhydrous silica, stearic 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. The lubricants and glidants may be present in the composition of the present invention in an amount ranging from about 0.05 % w/w to about 5 % w/w of the composition. Suitable plasticϊzers that may be used in the composition of the present invention include one or more of polyethylene glycol, triethyl citrate, triacetϊn, diethyl phthalate, dibutyl sebacetate, hydrogenated vegetable oil such as Lubritab, polyoxyethylene alkyl ethers such as Cremophor and the like and mixtures thereof. The plasticϊzers may be present in the composition of the present invention in an amount ranging from about 1 % w/w to about 10 % w/w of the composition.

Suitable stabilizers include one or more of antioxidants, buffers, acids and the like may also be used in the composition of the present invention. The stabilizers may be present in the composition of the present invention in an amount ranging from about 0.05 % w/w to about 10 % w/w of the composition.

Suitable coloring agents include any FDA approved colors for oral use.

The carvedilol or a pharmaceutically acceptable salt thereof is applied as a suspension or a solution of the drug in an organic solvent system. The carvedilol or a pharmaceutically acceptable salt thereof can be applied over the inert cores as a suspension or a solution of the drug using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidϊzed bed processor; dip coating and the like. The carvedilol or its pharmaceutically 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 Pelletizatϊon Technology, (1989) pp. 50-54, ed. Isaac Ghebre-Sellassie, Marcel Dekker, Inc., New York and Basel). A suspension or a solution of the carvedilol or a pharmaceutically acceptable salt thereof is sprayed on the fluidizing bed of cores until the desired amount of drug loading or layering is achieved. The layering suspension or solution of carvedilol or a pharmaceutically acceptable salt thereof is formed by adding the active in selected solvent system. Binders such as povidone and other excipients or ingredients as is desirable or appropriate may be added to the suspension or solution. The carvedilol layered cores may then be coated with a second coating layer comprising enteric polymer or a mixture of enteric polymers. The second coating layer may be applied as suspension of the enteric polymers using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating and the like.

The second coating layer may then optionally be coated with the further coating layer comprising a suspension or a solution of carvedilol or a pharmaceutically acceptable salt thereof and/or the coating layer comprising enteric polymer or a mixture of enteric polymers using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating and the like.

Accordingly, the controlled release, multiple unit pharmaceutical compositions of the present invention comprising earvedilol or a pharmaceutically acceptable salt thereof may provide individual controlled release units comprising aforesaid one or more coating layer(s) and a dosage form combining a plurality of the same type of such individual controlled release units.

In an embodiment, the controlled release, multiple unit pharmaceutical compositions of carvedilol or a pharmaceutically acceptable salt thereof of the present invention may be filled in capsules or sachets. In another embodiment, the controlled release, multiple unit pharmaceutical compositions of carvediiol or a pharmaceutically acceptable salt thereof of the present 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.

In general, the process for the preparation of controlled release, multiple unit pharmaceutical composition of carvedilol or a pharmaceutically acceptable salt thereof, comprises: (a) providing a core; (b) coating at least a portion of the outer surface of the core (a) with a solution or suspension comprising carvedilol or a pharmaceutically acceptable salt thereof; (c) coating at least a portion of the outer surface of the first coating layer (b) with a second coating layer comprising one or more enteric polymers; and (d) optionally coating at least a portion of the outer surface of the second coating layer (e) with one or more coating layer(s) of the first coating layer (b) and/or second coating layer (c) to form individual units; and (e) combining a plurality of individual units in a dosage form. The dosage form as used herein refers to the controlled release, multiple unit pharmaceutical composition of the present invention, which may be chosen from dosage forms known in the art such as capsules, sachets, tablets and the like.

0 The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

EXAMPLE l -5 The controlled release, multiple unit pharmaceutical composition of the present invention may be prepared as given in Table 1.

Table 1 : Unicomponent system with no immediate release (IR) portion over controlled release portion 0

Sr.

Ingredients Qty

No. %w/w Category

(mg)/Capsule

Stage I: First coating layer

Core and first coating layer

Carvedilol 22.66 % of

1 80 Active Phosphate core

63.73 % of

2 CelpherePH305 225 Diluent core

3 Povidone K 30 24 6.79 % of core Binder

4 Crospovidone 24 6.79 % of core Disintegrant

5 Methanol qs Solvent

6 Methylene qs Solvent chloride

Stage II: Second coating layer

24.98 % of

1 EudrgϊtL100-55 8.82 Enteric polymer coating

34.98 % of

2 Eudrgit S 100 12.35 Enteric polymer coating

Hydrogenated 40.02 % of 3 14.13 Plasticizer vegetable oil coating

Methylene 4 qs Solvent chloride

Isopropyl 5 qs Solvent alcohol

Stage HI: Lubrication

0.73 % of total

1 Talc 2.91 Lubricant weight

Colloidal Silicon 0.73 % of total

2 2.91 Lubricant dioxide weight

Stage I: First coating layer

Carvedilol Phosphate was dissolved in methanol and methelytie chloride solvent system under strring. Then Povidone K 30 and Crospovidone were added in the same solution and stirred for 30 min. Drug layering was carried out on celphere CP 305 till desired weight gain and continuous stirring of coating dispersion was ensured during coating operation.

Stage II: Second coating layer

Eudragit L100-55 and Budragit SlOO were dispersed in isopropyl alcohol and hydrogenated vegatable oil was dispersed in methylene chloride in separate pots under strring till uniform suspension. Then Eudragit L100-55 and Eudragit SlOO containing solution was added in hydrogenated vegatable oil suspension. This coating dispersion was used to coat the drug layer of stage I till desired weight gain and continuous stirring of coating dispersion was ensured during coating operation.

Stage III: Lubrication and Encapsulation The coated pellets were then lubricated with talc and colloidal silicon dioxide & filled the lubricated pellets ϊπ the capsule.

EXAMPLE 2

The controlled release, multiple unit pharmaceutical composition of the present invention may be prepared as given in Table 2.

Table 2: Unicomponent system with IR portion over controlled release portion.

Sr. Qty fo. Ingredients (mg)/Capsule %w/w Category

Stage I: First coating layer

Core and first coating layer

Carvedilol

1 70 20.77 % of Active Phosphate core

2 Celphere PH 3O5 225 66.76 % of Diluent core 3 Povidone K 30 21 6.23 % of core Binder

4 Crospovidone 21 6.23 % of core Disintegrant

5 Methanol qs Solvent

Methylene

6 qs Solvent chloride

Stage II: Second coating layer

Eudragtt LlOO-

1 8.43 25.00 % of Enteric polymer

55 coating

2 Eudrgit SlOO 11.80 35.00 % of Enteric polymer coating

Hydrogenated

3 13.48 39.98 % of Plasticizer vegetable oil coating

4 Methylene qs Solvent chloride

Isopropyf

5 qs Solvent alcohol

Stage DI: Coaling layer (drug)

Carvedilol

1 10 76.92 % of Active Phosphate coating

2 Povidone K 30 3 23.07 % of Binder coating 3 Methanol qs Solvent

Methylene

4 qs Solvent chloride

Stage rV: Lubrication

1 Talc 2.91 0.74 % of total Lubricant weight

Colloidal Silicon

2 2.91 0.74 % of total Lubricant dioxide weight

Stage I: First coating layer

Carvedilol Phosphate was dissolved in methanol and methylene chloride solvent system under strring. Then Povidone K 30 and Crospovidone were added in the same solution and stirred for 30 min. Drag layering on celphere CP 305 was carried out till desired weight gain and continuous stirring of coating dispersion was ensured during coating operation.

Stage H: Second coating layer Eudragit L 100-55 and Eudragϊt SlOO were dispersed in ϊsopropyl alcohol and hydrogenated vegetable oil was dispersed in methylene chloride in separate pots under strring till uniform suspension. Then Eudragit L1G0-55 and Eudragit SlOO containing solution was added in hydrogenated vegatable oil suspension. This coating dispersion was used to coat the stage I pellets till desired weight gain and continuous stirring of coating dispersion was ensured during coating operation. Stage HI: Coating layer (drag)

Carvedϊlol phosphate was dissolved in methanol and methylene chloride solvent system. Povidone K30 was added to this solution under stirring. The stirring was continued till clear solution obtained. Drug layering on stage II pellets was carried out till desired weight gain achieved.

Stage IV: Lubrication and Encapsulation The coated pellets were lubricated with talc and colloidal silicon dioxide and filled the lubricated pellets in the capsule.

EXAMPLE 3

The controlled release, multiple unit pharmaceutical composition of the present invention may be prepared as given in Table 3,

Table 3 : Unicomponent system with multiple drug layering and coatings.

Sr. Qty

Ingredients %w/w Category No. (mg)/Capsule

Stage I: First coating layer Core and first coating layer

Carvedύol

1 40 13.84 % of Active

Phosphate core

2 Celphere C 305 225 77.85 % of Diluents core

3 Povidone K30 12 4,15 % of core Binder

4 Crospovidone 12 4.15 % of core Disitegrants

5 Methanol qs Solvent Methylene qs Solvent chloride

Stage H: Second coating layer

Eudrgit Ll 00-55 7.23 25.00 % of Enteric polymer coating

Eudrgit SlOO 10.12 35.00 % of Enteric polymer coating

Hydrogenated

11.56 39.98 % of Plasticizer vegetable oil coating

Methylene qs Solvent chloride

Isopropyle qs Solvent alcohol

Stage UI: coating layer (drug)

Carvedilol

30 62.50 % of Active Phosphate coating

Povidone K30 9 18.75 % of Binder coating Crospovidone 9 1S.75 % of Disintegrant coating

Methanol qs Solvent

Methylene qs Solvent chloride

Stage IV: Coating layer (enteric polymers)

Eudrgit Ll 00-55 2.88 60.00 % of Enteric polymer coating

Hydrogenated 1.92 40.00 % of Plasticizer vegetable oil coating

Methylene qs Solvent chloride

Isopropyle qs Solvent alcohol

Stage V: coating layer (drag)

Carvedilol 10 76.92 % of Active coating Phosphate

2 Povidone K30 3 23.07 % of Binder coating 4 Methanol qs Solvent

Methylene

5 qs Solvent chloride

Stage VI: Lubrication

1 Talc 2.87 0.73 % of total Lubricant weight

Colloidal Silicon

2 2.87 0.73 % of total Lubricant dioxide weight

Stage I: First coating layer

Carvedilol Phosphate was dissolved in methanol and methylene chloride solvent system under storing. Then Povidone K 30 and Crospovϊdone were added in the same solution and stirred for 30 min. Drag layering was carried out on celphere CP 305 till desired weight gain and continuous stirring of coating dispersion was ensured during coating operation.

Stage II: Second coating layer Eudragit L100-55 and Eudragit SlOO were dispersed in isopropyl alcohol and hydrogenated vegetable oil was dispersed in methylene chloride in separate pots under strring till uniform suspension. Then Eudragit L 100-55 and Eudragit SlOO containing solution was added in hydrogenated vegatable oil suspension. This coating dispersion was used to coat the stage I pellets till desired weight gain and continuous stirring of coating dispersion was ensured during coating operation.

Stage HI: Coating layer (drug)

Carvedilol Phosphate was dissolved in methanol and methylene chloride solvent system under strring. Then Povidone K 30 and Crospovϊdone were added in the same solution and stirred for 30 min. Drug layering was carried out on stage II pellets till desired weight gain and continuous stirring of coating dispersion was ensured during coating operation. Stage IV: Coating layer (enteric polymers)

EudragitLl 00-55 was dispersed ϊπ isopropyl alcohol and hydrogenated vegatable oil was dispersed in methylene chloride in separate pots under strring till uniform suspension.

Then Eudragit L 100-55 containing solution was added in hydrogenated vegatable oil suspension. This coating dispersion was used to coat the stage HI pellets till desired weight gain and continuous stirring of coating dispersion was ensured during coating operation.

Stage V: Coating layer (drug)

Carvedilol phosphate was dissolved in methanol and methylene chloride solvent system. Povidone K30 was added to this solution under stirring. The stirring was continued till clear solution obtained. Drug layering on stage IV pellets was carried out till desired weight gain achieved.

Stage VI: Lubrication and encapsulation

The coated pellets were lubricated with talc and colloidal silicon dioxide and filled the lubricated pellets in the capsule.

EXAMPLE 4

The controlled release, multiple unit pharmaceutical composition of the present invention as prepared in example 1 was subjected to dissolution. The results are given ϊn Table 4.

Media 0. IN HCL

Apparatus USP Type π

Agitation 100 RPM

Volume 900 ml

Table 4

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 without departing from the spirit of or exceeding the 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

Claims

Claims:

1. A controlled release, multiple unit pharmaceutical composition comprising a plurality of the same type of controlled release units, wherein each unit comprises, (a) a core;

(b) a first coating layer surrounding the outer surface of the core (a), wherein the coating layer comprises carvedilol or a pharmaceutically acceptable salt thereof;

(c) a second coating layer surrounding the outer surface of the first coating layer (b) comprising one or more enteric polymers; and (d) optionally, one or more additional coating layer(s) which are the first coating layer (b) and/or second coating layer (c) surrounding the outer surface of the second coating layer (c).

2. The controlled release, multiple unit pharmaceutical composition of claim 1, wherein the first coating layer (b) comprises depositing a suspension of carvedilol or a pharmaceutically acceptable salt thereof.

3. The controlled release, multiple unit pharmaceutical composition of claim 1, wherein the first coating layer (b) comprises depositing a solution of carvedilol or a pharmaceutically acceptable salt thereof.

4. The controlled release, multiple unit pharmaceutical composition of claim 3, wherein the first coating layer (b) comprising depositing the solution of carvedilol or a pharmaceutically acceptable salt thereof, is prepared in a methanol-methylene chloride solvent system.

5. The controlled release, multiple unit pharmaceutical composition of claim 4, wherein the carvedilol or a pharmaceutically acceptable salt thereof in the first coating layer (b) is in amorphous form.

6. The controlled release, multiple unit pharmaceutical composition of claim 1, wherein the core (a) includes one or more of sugar, a πoπ-pareiϊ seed, mϊcrocrystalline cellulose, celphere, sand silicon dioxide, glass, plastic, polystyrene, hydroxypropyl methylcellulose and the like and mixtures thereof.

7. The controlled release, multiple unit pharmaceutical composition of claim 1, wherein the second coating layer (c) comprises one or more enteric polymers selected from cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; methacryϊic acid copolymers such as Eudragit L 100-55, Eudragit L30 D-55, Eudragit L 100, Eudragit L 12,5, Eudragit S 100, Eudragit S 12,5, and Eudragit FS 30 D and the like and mixtures thereof.

8. The controlled release, multiple unit pharmaceutical composition of claim 7, wherein the enteric polymers are used in amounts ranging from about 2 % w/w to about 25 % w/w.

9. The controlled release, multiple unit pharmaceutical composition of claim 1, wherein the first coating layer (b), the second coating layer (c) and the optional one or more additional coating layer(s) (d) include one or more pharmaceutically acceptable excipients.

10. The controlled release, multiple unit pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable excϊpϊents include binders, diluents, disintegrants, lubricants, glidants, plasticizers, stabilizers, and coloring agents.

11. The controlled release, multiple unit pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a tablet, a capsule, a sachet and the like.

12, The controlled release, multiple unit pharmaceutical composition of claim 11, wherein the pharmaceutical composition is a capsule.

13. A process for preparing a controlled release, multiple unit pharmaceutical composition comprising a plurality of the same type of controlled release units comprising

(a) providing a core;

(e) combining a plurality of the individual units in a dosage form.