FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
An extended release, pharmaceutical composition comprising diltiazem.
2. APPLICANT (S)
(a) NAME: Micro Labs Limited.
(b) NATIONALITY: Indian
(c) ADDRESS: CTS No. 73, Saki Estate, Off Chandivali Road, Chandivali,
Kurla (W), Mumbai - 400 072.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an extended release pharmaceutical composition comprising diltiazem. Particularly, the present invention provides an extended release pharmaceutical composition in the form of a tablet or a capsule comprising release controlling agent(s) and a process for preparing the same.
4. DESCRIPTION (Description shall start from the next page.)
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention:
The present invention relates to an extended release pharmaceutical composition comprising diltiazem. Particularly, the present invention provides an extended release pharmaceutical composition in the form of a tablet or a capsule comprising diltiazem, release controlling agent(s) and a process for preparing the same.
Background of the invention:
Cardiovascular diseases are a class of diseases that involve the heart and the blood vessels. The causes of cardiovascular disease are diverse but atherosclerosis and/or hypertension are the most common. Hypertension is a chronic medical condition which is characterized by high blood pressure. Angina is commonly defined as chest pain which is characterized by obstruction of coronary arteries.
Diltiazem has been used as a pharmaceutical agent to treat hypertension and angina. It is a calcium antagonist and hence blocks the influx of calcium ions in smooth and cardiac muscles and thus exerts potent cardiovascular effects. It is a benzothiazine derivative which is chemically described as c/s-(+)-[2-(2-dimethylaminoethyl)-5-(4-methoxy phenyl) -3-oxo-6-thia-2-azabicyclo [5.4.0] undeca-7, 9, 11-trien-4-yl] ethanoate and has the following structure:
Diltiazem is available as Cardizem CD® (by Biovail Laboratories International) in US market. It is once-a-day extended-release capsule containing 120 mg, 180 mg, 240 mg, 300 mg and 360 mg diltiazem hydrochloride which is used for the treatment of hypertension and for the management of chronic stable angina and angina due to coronary artery spasm.

Cardizem CD® contains the following inactive ingredients: the 120 mg, 180 mg, 240 mg, and 300 mg capsules contain acetyl tributyl citrate, ammonio methacrylate copolymer dispersion, black iron oxide (300 mg), castor oil, ethyl cellulose, FD&C Blue #1, fumaric acid, gelatin, silicon dioxide, simethicone, starch, stearic acid, sucrose, talc, titanium dioxide and white wax. The 360 mg capsule contains acetyl tributyl citrate, ammonio methacrylate copolymer dispersion, diethyl phthalate, FD&G Blue #1, gelatin, povidone, simethicone, sodium lauryl sulfate, starch, sucrose, talc and titanium dioxide.
US4894240 discloses diltiazem pellet formulation consisting of core containing diltiazem and a multi layer membrane to give a suitable extended release profile.
US5439689 discloses a method of treatment of cardiovascular disorders with diltiazem formulation having two separate components (Rapid release and delayed release).
US5470584 and US5296497 disclose extended release pharmaceutical compositions of diltiazem having two separate rapid and delayed release components.
US7108866 discloses chronotherapeutic diltiazem formulations that contain a water soluble and diffusible polymer coating on a core. The water soluble and diffusible polymer coating consists of at least one hydrophilic polymer and at least one water, acid or base insoluble neutral acrylic polymer.
Still, there is need of a novel extended release pharmaceutical composition comprising diltiazem.
Summary of the invention:
The present invention relates to an extended release pharmaceutical composition comprising diltiazem and release controlling agent(s).

In an embodiment, the present invention provides an extended release pharmaceutical composition comprising diltiazem and release controlling agent(s) selected from Ammonio Methacrylate Copolymer, Type B and/ or ethyl cellulose.
In an aspect of the embodiment, the extended release pharmaceutical composition comprises Ammonio Methacrylate Copolymer, Type B and ethyl cellulose in a weight ratio of 0.5:1 to 5:1.
In another aspect of the embodiment, the extended release pharmaceutical composition comprises diltiazem and Ammonio Methacrylate Copolymer, Type B in a weight ratio of 1:1 to 10:1, diltiazem and ethyl cellulose in a weight ratio of 5:1 to 20:1.
In yet another aspect of the embodiment, the extended release pharmaceutical composition comprises Ammonio Methacrylate Copolymer, Type B which in the form of an aqueous dispersion.
In another aspect of the embodiment, the extended release pharmaceutical composition comprises pharmaceutical^ acceptable inert excipients namely diluents, lubricants, glidants, binders, wetting agents, antifoaming agents, solvents and plasticizers.
In yet another aspect of the embodiment, the extended release pharmaceutical composition has an in vitro dissolution profile as follows:
0.1% to 20% in 2 hours,
15% to 50% in 4 hours,
50% to 90% in 12 hours and
80% to 100% in 24 hours when measured using the USP type II dissolution testing apparatus using 900 ml of aqueous medium comprising phosphate buffer at pH 6.8 at about 37°C, being stirred at 100 rpm.

In another aspect of the embodiment, the extended release pharmaceutical composition is in the form of a tablet or a capsule.
In another embodiment, the extended release pharmaceutical composition comprises diltiazem in an amount of 30% to 70% by weight, inert cores in an amount of 1% to 5% by weight, hypromellose in an amount of 1% to 10% by weight, polysorbate 80 in an amount of 1% to 6% by weight, talc in an amount of 1% to 15% by weight, ethyl cellulose in an amount of 1% to 15% by weight, Triethyl Citrate in an amount of 1% to 6% by weight, Ammonio Methacrylate Copolymer, Type B in an amount of 1% to 20% by weight, Simethicone Emulsion USP (30%) in an amount of 0.005% to 0.015% by weight.
In yet another embodiment, the extended release pharmaceutical composition is prepared by a process wherein a solution of diltiazem and binder is layered on inert cores, which are then coated with pharmaceutical^ acceptable inert excipients.
Detailed description of the invention:
The present invention relates to an extended release pharmaceutical composition comprising diltiazem and release controlling agent(s).
The terms used in the specification are. defined as follows.
The term 'extended release pharmaceutical composition' denotes a composition which shows a prolonged and a constant release for a period of 24 hours.
The term 'diltiazem' includes Diltiazem or its pharmaceutically acceptable salt. The pharmaceutically acceptable salt of diltiazem includes hydrochloride, hydrobromide, sulfate, phosphate, lactate, citrate, tartrate, malate, maleate, fumurate, ascorbate, gulconate, asparate, salicylate, and the like. The hydrochloride salt is used preferably.

The term "active ingredient" (used interchangeably with "active" or "active substance" or "drug") as used herein includes diltiazem or its pharmaceutically acceptable salt.
The term "pharmaceutically acceptable inert excipients", denotes any of the components of a pharmaceutical composition other than the active and which are approved by regulatory authorities or are generally 'regarded as safe' for human or animal use.
The term "inert core" as described herein is intended to include anything below the seal coat or when the seal coat is absent, anything below the extended release coat.
In an embodiment, the present invention provides an extended release pharmaceutical composition comprising diltiazem and release controlling agent(s) selected from Ammonio Methacrylate Copolymer, Type B and/ or ethyl cellulose.
Ammonio Methacrylate Copolymer, Type B is a copolymer of ethyl acrylate, methyl methacrylate and has low content of methacrylic acid ester with quaternary ammonium groups. The ammonium groups are present as salts and make the polymers permeable. Ammonio Methacrylate Copolymer, Type B is present as an aqueous 30% dispersion. Chemically it is Poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1. Ammonio Methacrylate Copolymer, Type B is widely used as an agent to extend the release in a pharmaceutical composition.
Ethyl cellulose is an ethyl ether of cellulose which is a long-chain polymer of b-anhydroglucose units joined together by acetal linkages. Ethyl cellulose is chemically known as cellulose ethyl ether and is widely used in oral and topical pharmaceutical compositions. Ethyl cellulose is hydrophobic which is used to extend the release in a pharmaceutical composition.

In an aspect of the embodiment, the extended release pharmaceutical composition comprises diltiazem and Ammonio Methacrylate Copolymer, Type B and ethyl cellulose in a weight ratio of 0.5:1 to 5:1 preferably in weight ratios of 0.5:1,1:1, 1.2:1, 1.8:1, 2:1, 2.5:1, 4:1 or 5:1 and more preferably in the weight ratios of 1.2:1, 1.8:1 or 2:1.
In yet another aspect of the embodiment the extended release pharmaceutical composition comprises diltiazem and Ammonio Methacrylate Copolymer, Type B in a weight ratio of 1:1 to 10:1, preferably in the weight ratios of 1:1, 2:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 6:1, 7:1, 7.5:1, 8:1 or 9:1 and more preferably in the weight ratios of 3.5:1, 4.5:1 or 5.8:1.
The extended release pharmaceutical composition comprises diltiazem and ethyl cellulose in a weight ratio of 5:1 to 20:1 preferably in the weight ratios of 5:1,6:1,6.4:1, 7.6:1, 8.3:1, 8.8:1, 9:1, 9.5:1, 10.5:1, 11:1, 12:1, 15:1, 17.5:1 or 20:1 and more preferably in the weight ratios of 7.6:1, 8.3:1 or 8.8:1.
In yet another aspect of the embodiment, the extended release pharmaceutical composition comprises Ammonio Methacrylate Copolymer, Type B which is in the form of an aqueous dispersion.
In another aspect of the embodiment, the extended release pharmaceutical composition comprises pharmaceutically acceptable inert excipients.
Examples of pharmaceutically acceptable inert excipients include, but are not limited to diluents, lubricants, binders, wetting agents, antifoaming agents, solvents and plasticizers. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.
Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc,' microcrystalline

cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate and other materials known to one ordinarily skilled in the art and mixtures thereof.
Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc and other materials known to one ordinarily skilled in the art and mixtures thereof.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one ordinarily skilled in the art and mixtures thereof.
Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trade marks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth and other materials known to one ordinarily skilled in the art and mixtures thereof.
Wetting agents include, but are not limited to PEG-20-glyceryl stearate, PEG-40 hydrogenated castor oil, PEG 6 corn oil, lauryl macrogol-32 glyceride stearoyl macrogol glyceride, polyglyceryl-10 mono dioleate, Propylene glycol dioctanoate, Propylene glycol caprylate/caprate, Glyceryl monooleate, Glycerol monolinoleat, Glycerol monostearate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, PEG-20 sorbitan monostearate, PEG-20 sorbitan monopalmitate, PEG-4 lauryl ether, Sucrose distearate, Sucrose

monopalmitate, polyoxyethylene-polyoxypropylene block copolymer, polyethylene glycol 660 hydroxystearate, Sodium lauryl sulphate, Sodium dodecyl sulphate, Dioctyl suphosuccinate, L-hydroxypropyl cellulose, hydroxylethylcellulose, hydroxy propylcellulose, Propylene glycol alginate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, betains, polyethylene glycol, d-a-tocopheryl polyethylene glycol 1000 succinate and other materials known to one ordinarily skilled in the art and mixtures thereof.
Antifoaming agents include, but are not limited to polydimethylsiloxane, simethicone, other silicones, stearates, alcohols, glycols and other materials known to one ordinarily skilled in the art and mixtures thereof.
Solvents include, but are not limited to purified water, acetone, ethyl alcohol and other materials known to one ordinarily skilled in the art and mixtures thereof.
Plasticizers include, but are not limited to acetylated monoglycerides; acetyltributyl citrate, butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; acetyltriethyl citrate, polyethylene glycols; castor oil; rape seed oil, olive oil, sesame oil, triethyl citrate; polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters, gylceroi triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate, diethylmalonate, dibutylphthalate, dibutylsebacate, glyceroltributyrate, polyols (e.g. polyethylene glycol) of various molecular weights and other materials known to one ordinarily skilled in the art and mixtures thereof.

It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions of the present invention. One or more of these additives can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation without any undue burden.
The amount of each type of additive employed may vary within ranges conventional in the art.
In an embodiment, the pharmaceutical composition is in the form of solid dosage form. The term solid dosage form includes tablet, capsules, pills, granules, tablets in capsules, caplets, min-tablets or a combination thereof. In an aspect of the embodiment, the extended release pharmaceutical composition is a tablet or a capsule.
In yet another embodiment, the extended release pharmaceutical composition is prepared by a process wherein a solution of diltiazem and binder is layered on inert cores, which are then coated by pharmaceutical^ acceptable inert excipients.
In yet another aspect of the embodiment, the extended release pharmaceutical composition has an in vitro dissolution profile as follows:
0.1% to 20% in 2 hours,
15% to 50% in 4 hours,
50% to 90% in 12 hours and
80% to 100% in-24 hours when measured using the USP type II dissolution testing apparatus using 900 ml of aqueous medium comprising phosphate buffer at pH 6.8 at about 37°C, being stirred at 100 rpm.

In another embodiment, the extended release pharmaceutical composition comprises diltiazem in an amount of 30% to 70% by weight, inert cores in an amount of 1% to 5% by weight, hypromellose in an amount of 1% to 10% by weight, polysorbate 80 in an amount of 1% to 6% by weight, talc in an amount of 1% to 15% by weight, ethyl cellulose in an amount of 1% to 15% by weight, Triethyl Citrate in an amount of 1% to 6% by weight, Ammonio Methacrylate Copolymer, Type B in an amount of 1% to 20% by weight, Simethicone Emulsion USP (30%) in an amount of 0.005% to 0.015% by weight.
In yet another embodiment, the extended release pharmaceutical composition is prepared by a process wherein a solution of diltiazem and binder is layered on inert cores, which are then coated with pharmaceutically acceptable inert excipients.
The inert core may comprise inert non-pareils which are conventionally used in pharmaceutical industry and are readily available. The inert nonpareils may be of any pharmaceutically acceptable excipient such as starch, sugar, microcrystalline cellulose, vegetable gums, waxes, and the like. Preferably, the inert non-pareils are of starch and sugar. The size of the inert non-pareils may vary from 0.1 mm-2 mm. The core may also be prepared by techniques such as granulation or extrusion-spheronization. For example, the core may be prepared by mixing at least one pharmaceutically acceptable excipient and diltiazem, moistening the mixture with water or a solvent, granulating and subsequently drying to obtain granules which may be used as the core. Alternatively, such granules may be compressed into a tablet, which may be used as the core. The core may be prepared by mixing at least one pharmaceutically acceptable inert excipients and diltiazem, wetting with water or organic solvent and mixing in a high shear granulator to form a homogeneous wet mass, extruding the wet mass to form extrudates which are subsequently spheronized to form spheres which may be used as the core. The core may be present in an amount ranging from 10% to 90% by weight of the composition.

The foregoing examples are illustrative embodiments and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the claims.
Example 1:

Ingredient Quantity (mg)
Inert cores 5-25
Diltiazem 120-360
Hypromellose 2910 20-50
Polysorbate 80 10-25
Talc 30-80
Ethyl cellulose (10 mPas) 25-60
Triethyl Citrate NF 10-35
Ammonio Methacrylate Copolymer, Type B 45-85
Simethicone Emulsion USP (30%) 0.03-0.15
Purified Water q.s.
Isopropyl alcohol q.s.
Dichloromethane q.s.
Isopropyl alcohol q.s.
Manufacturing Process:
1. Preparation of solution of diltiazem:
Polysorbate 80 was dissolved in (sopropyl alcohol under stirring. Hypromellose 2910 was dispersed into the solution under stirring. Purified water was added to the solution arid the solution was stirred to form a clear solution. Diltiazem was added slowly into the solution and the solution was stirred to form a clear solution. Talc was added to the solution. This solution was layered on the inert cores.
2. Preparation of solution of Ammonio Methacrylate Copolymer, Type B:

Talc was dispersed in five fold quantity of purified water in one container. Ammonio Methacrylate Copolymer, Type B dispersion was taken in a separate container. Simethicone emulsion and triethyl citrate was added to the same. Dispersion of talc was added to the dispersion of Ammonio Methacrylate Copolymer, Type B under stirring. It was layered on the drug coated inert cores.
3. Preparation of solution of ethyl cellulose:
Ethyl cellulose was dispersed into Isopropyl alcohol under stirring. Dichloromethane and triethyl citrate were added under stirring till a clear solution was obtained. It was layered on the coated pellets.
Example 2:

SN Name of the Ingredient Quantity (mg)
Part 1:
A Seal Coating
1 Sugar Sphere 30/35# 50.00
2 Ethylcellulose 10cps 2.00
3 Triethyl citrate 0.50
4 Isopropyl Alcohol Qs
5 Dichloromethane Qs
Seal Coated pellets 52.50
B Drug Loading-I
1 Diltiazem 120.00
2 Hypromellose (5cps) 12.00
3 Polysorbate 80 0.668
4 Purified Talc 1.20
5 Purified Water Qs
Drug Loaded Pellet-I 186.37
C Extended Release Coating I
1 Ethylcellulose 10cps 16.77
2 Triethyl citrate 1.677
3 Isopropyl Alcohol Qs

4
Dichloromethane Qs
Extended Release Coated Pellet-I
D Drug Loading-ll
1 Diltiazem 120.00
2 Hypromellose (5cps) 12
3 Purified Talc 1.2
4 Purified Water Qs
Drug Loaded Pellet-I I 338.02
E Extended Release Coating II
1 Ethyl cellulose 45cps 38.027
2 Klucel LF 7.605
3 Triethyl citrate 5.07
4 Isopropyl Alcohol Qs
5 Dichloromethane Qs
Extended Release Coated Pellet-ll 388.72
u_ Drug Loading-Ill
1. Diltiazem 120.0
2. Hypromellose (5cps) 12.0
3, Purified Talc 1.2
4. Purified Water Qs
Drug Loaded Pellet-Ill 133.2
Part II:
G Enteric coated-l (15%)
1. EudragitRSPO 34.58
2. Eudragit RL PO 1.82
3. Triethyl citrate 5.228
4. Purified Talc 10.656
5. Acetone Qs
6. Isopropyl Alcohol Qs
7. Purified Water Qs
Enteric coated pellet-l 185.5
Part III:

H
Capsule Filling
1. Extended Release Coated Pellet-ll 388.72
2. Enteric coated pellet-l 185.5
3. Capsule Size "00" 119.0
Total Capsule weight 693.22

We claim:
1. An extended release pharmaceutical composition comprising diltiazem and release controlling agent(s) selected from Ammonio Methacrylate Copolymer, Type B and/ or ethyl cellulose.
2. The extended release pharmaceutical composition according to claim 1 wherein ratio of diltiazem to ethyl cellulose is 0.5:1 to 2.5:1.
3. The extended release pharmaceutical composition according to claim 1 wherein ratio of diltiazem to Ammonio Methacrylate Copolymer, Type B is 2.5:1 to 7.5:1 & that of diltiazem to ethyl cellulose is 5.5:1 to 10.5:1.
4. The extended release pharmaceutical composition according to claim 1 wherein the Ammonio Methacrylate Copolymer, Type B is in the form of an aqueous dispersion.
5. The extended release pharmaceutical composition according to claim 1 wherein pharmaceutically acceptable excipients comprise diluents, lubricants binders and plasticizers.
6. The extended release pharmaceutical composition according to claim 1 which releases diltiazem into phosphate buffer at following rates when measured using the USP type II apparatus at 100 rpm in 900ml phosphate buffer:
1. between about 0.1 % to 20% in 2 hours
2. between about 15% to 50% in 4 hours
3. between about 50% to 90% in 12 hours
4. between about 80% to 100% in 24 hours.
7. The extended release pharmaceutical composition according to claim 1 is a tablet or a capsule.
8. The extended release pharmaceutical composition comprises following ingredients:

Ingredient Quantity (%w/w)
Inert cores 30% to 70%
Diltiazem 1%to5%
Hypromellose 2910 1%to10%
Polysorbate 80 1%to6%-
Talc 1%to15%
Ethyl cellulose (10 mPas) 1 % to 15
Triethyl Citrate NF 1%to6%
Ammonio Methacrylate Copolymer, Type B 1%to20%
Simethicone Emulsion USP (30%) 0.005% to 0.015%
Purified Water q.s.
Isopropyl alcohol q.s.
Dichloromethane q.s.
Isopropyl alcohol q.s.
9. A process for preparing an extended release pharmaceutical composition wherein a solution of diltiazem and binder is layered onto inert cores which are then coated with pharmaceutically acceptable excipients.
10. An extended release pharmaceutical composition as described herein.