FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
CONTROLLED RELEASE DILTIAZEM COMPOSITION
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to a controlled release diltiazem pharmaceutical composition comprising a) delayed release pellets comprising diltiazem or salts thereof along with pharmaceutically acceptable excipients and b) rapid release minitablets.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention relates to controlled release diltiazem composition comprising a) delayed release pellets and b) rapid release minitablets.
Diltiazem hydrochloride is a calcium ion influx inhibitor (slow channel blocker or
calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-benzothiazepin-
4(5H)one,3-(acetyloxy)-5-[2-(dimethylamino) ethyl]-2,3-dihydro-2-(4-
methoxyphenyl)-,monohydrochloride,(+)-cis-. The chemical structure is:

FORMULA I
Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol, and chloroform. Commercially it is marketed as extended release capsules, tablets, injection and immediate release tablets. Diltiazem hydrochloride is indicated for the treatment of hypertension and for the management of chronic stable angina and angina due to coronary artery spasm.
U.S Patent Nos. 3,562,257 discloses the compound diltiazem and its salts thereof. Diltiazem is well absorbed from the gastrointestinal tract and is subjected to an extensive first pass effect giving an absolute bioavailability of 40% (when compared with intravenous administration.) At therapeutic doses, approximately 60% of the administered diltiazem is metabolized before the compound has had a chance to reach its site of action.


Controlled release formulations of diltiazem are designed to release significant quantities of drug only at specific timed intervals. If the release occurs at appropriate times, therapeutic levels are maintained over an extended dosing period such as 12 or 24 hours.
Controlled release compositions of diltiazem are known in the prior art. Several patents and applications including US patent numbers 5,002,776; 5,286,497; 5,470,584; 5,529,791; 5,422,123; 5,288,505; 7,108,866; 6,270,805; 5,830,503; 5,834,023; 5,567,441; 5,458,888; 5,419,917; 6,162,463; 5,229,135; 7,067,151; 6,214,385; 6,033,687; 5,834,024; US RE35903; 4,963,365; 5,112,621; 5,472,710; 5,344,657; 5,000,962; 5,601,845; 5,670,172; 5,529,790; 5,968,552; 6,660,296; 6,383,516; 6,228,395; 5,945,125 and US application numbers 2004176352; 20060153914; 2007036856; 2007042041; 2007071820 and 2006292221.
Several other patents disclose the use of controlled release compositions of diltiazem for the treatment of various heart disorders. Such patents and applications include US patent number 5,364,620; 5,439,689; 5,219,621; 5,336,504 and 5,508,044
US patent numbers 6,524,620; 5,616,345; 5,622,716; 5,252,337 and 5,709,885 disclose the process of preparing control release pharmaceutical compositions containing diltiazem.
The present inventors while working on pharmaceutical compositions of diltiazem have surprisingly found that control release pharmaceutical compositions comprising diltiazem or salts thereof may comprise delayed release pellets and rapid release minitablet. The delayed release part having pellets wherein the pellets comprise an inert core having the following sequence of coatings a) a drug layering b) an extended release coating c) optionally a protective coating, d) second drug layering and e) external coating. Rapid release part comprises


minitablets comprising diltiazem or salts thereof along with rate controlling polymer. Both these parts in a ratio varying between 1:100 and 100:1 constitute a controlled release diltiazem pharmaceutical composition.
In one of the aspects of present invention there is provided, a controlled release diltiazem pharmaceutical composition comprising:
a) delayed release part comprising an inert core which having the following sequence of coatings i) a drug layering ii) an extended release coating iii) optionally a protective coating, iv) second drug layering and v) external coating,
b) rapid release part comprising tablets of diltiazem wherein the said tablets comprise diltiazem or salts thereof and rate controlling agent.
The term "delayed release part" refers to the pellets that can exhibit a dissolution profile when measured in a type 2 dissolution apparatus (paddle) in 900 ml of 0.1N HCI at 100 rpm: a) from 0-50% of diltiazem is released after 12 hours; b) not less than 50% of diltiazem is released after 18 hours; and e) not less than 85% of total diltiazem is released after 30 hours.
The term "rapid release part" refers to the tablets that can exhibit a dissolution profile when measured in a type 2 dissolution apparatus (paddle) in 900 ml of 0.1 N HCI at 100 rpm: a) from 0-50% of diltiazem is released after 2 hours; b) not less than 80% of diltiazem is released after 6 hours; and e) not less than 85% of total diltiazem is released after 8 hours.
The term "controlled release diltiazem pharmaceutical composition" used herein refers to the blend of "delayed release part" and "rapid release part" wherein both the parts are present in a ration varying between 1:100 and 100:1.
The controlled release diltiazem pharmaceutical composition exhibits the following in-vitro dissolution pattern when measured in a type 2 dissolution


apparatus (paddle) in 900 ml of 0.1 N HCI at 100 rpm: a) from 0-50% of total diltiazem is released after 6 hours; b) from 10-50% of total diltiazem is released after 12 hours; c) from 20-70% of total diltiazem is released after 18 hours; d) not less than 55% of total diltiazem is released after 24 hours; and e) not less than 75% of total diltiazem is released after 30 hours.
The controlled release pharmaceutical composition wherein diltiazem or salts thereof comprises diltiazem hydrochloride.
The pharmaceutical composition of this invention contains 100 mg to 600 mg of diltiazem hydrochloride.
The rapid release part of the controlled release diltiazem pharmaceutical composition can be prepared by conventional methods of preparation like aqueous or non-aqueous wet granulation, direct compression, melt granulation or dry granulation.
The powder blend of diltiazem and rate controlling agent along with intragranular pharmaceutical^ acceptable excipients may be granulated by using aqueous or non-aqueous solvent. The granules are dried and passed through the sieve. The granules so obtained may be mixed with extragranular pharmaceutically acceptable excipients. The granules may be compressed using appropriate tooling to formulate tablets. The tablet may be optionally coated with a functional and/or non-functional coating.
Alternatively, the rapid release part may be prepared by drug granulation method wherein, the blend of diltiazem, rate controlling agent and intragranular excipients may be compacted followed by sizing the compacts in to granules. Granules thus obtained are mixed with extragranular pharmaceutically acceptable excipients, lubricated and compressed to tablets. The tablet may be optionally coated with a functional and/or non-functional coating.


The delayed release part of the controlled release diltiazem pharmaceutical composition comprises inert core having the following sequence of coatings a) a drug layering b) an extended release coating c) a protective coating, d) second drug layering and e) external coating.
The delayed release part of the controlled release diltiazem pharmaceutical composition can be prepared by coating a suspension of diltiazem, binder and other pharmaceutically acceptable excipients on an inert core. After drug layering the pellets are sized to get uniform size pellets. The rate-controlling polymer along with pharmaceutically acceptable excipients is dispersed in a suitable solvent. This suspension of rate-controlling polymer is applied on the inert core bearing drug layer. The polymer coating is cured for 24 h at 40°C. The protective coat comprises the step of coating a suspension of film forming polymer along with pharmaceutical excipients. Similarly the suspension of the drug, binder and pharmaceutical acceptable excipients is applied second time on the protective coating followed by the final external coating comprising film-forming polymer along with pharmaceutically acceptable excipients. The pellets so formed are cured for 24 h at 40°C and sized to get uniform size pellets.
The delayed release part of the controlled release pharmaceutical composition comprises inert core. Suitable inert cores may be selected from sugar seeds or non-pareils. Other example of inert cores is microcrystalline cellulose spheres commercially available under the trade name Celphere.
The pharmaceutically acceptable rate controlling agent can be selected from a group comprising of one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers, and mixtures thereof. Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum, ghatti gum, agar, gum arabic, galactomannan, irish moss, carrageenan xylogalactan, glucomannan and other


carbohydrate gums having similar properties. Suitable polyuronic acid salts
include one or more of alkali metal salts of alginic acid or pectic acid and
mixtures thereof. Suitable alkali metal salts of alginic acid that may be used
include one or more of sodium alginate, potassium alginate, ammonium alginate,
propylene glycol alginate and other suitable alkali metal salts of alginic acid.
Suitable cellulose ethers include one or more of methylhydroxypropylcelluloses,
hydroxyethylcelluloses, hydroxypropylcelluloses, methylcelluloses,
ethylcelluloses, and carboxymethylcelluloses and other suitable cellulose ethers. Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name carbopol. Pharmaceutically acceptable acrylic polymer may be include one or more, but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly( methacrylic acid anhydride), and glycidyl methacrylate copolymers. The pharmaceutically acceptable rate controlling agent can also be selected from a group comprising of one or more of natural or synthetic waxes, fatty acids, fatty alcohols, fatty acid esters, fatty acid glycerides including mono-, di-and tri-glyceride, hydrocarbons, hydrogenated fats, hydrogenated castor oils and hydrogenated vegetable oils, can be used. Said melt granulating agent, though not particularly limited, include cetostearyl alcohol, stearyl alcohol, cetyl alcohol, myristyl alcohol and lauryl alcohol, hydrogenated vegetable oil, glyceryl monostearate, glycerol monooleate, acetylated mono glyceride, tristearin, tripalmitin, cetyl ester wax, glyceryl palmitostearate and glyceryl behenate, microcrystalline wax, beeswax, camauba wax, glyco wax and castor wax.


Pharmaceutical^ acceptable excipients may comprise one or more of fillers, binders, disintegrants, lubricants, glidants, plastisizer, anti-tacking agent, aqueous or non-aqueous solvents, film forming polymers and the like.
Suitable binders may be one or more selected from a group of starch, sugars, gums, low molecular weight polyvinylpyrrolidone, hydroxy propyl methyl cellulose and hydroxypropyl cellulose and the like.
Suitable fillers may be one or more of lactose, dicalcium phosphate, microcrystalline cellulose, mannitol and the like.
Suitable lubricants may be one or more talc, magnesium stearate, calcium Stearate, glyceryl behenate polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate and the like.
Suitable glidants may be one or more of, colloidal silicon dioxide, talc, magnesium stearate, calcium stearate and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable aqueous or non-aqueous solvents may be one or more selected from a group comprising water, isopropyl alcohol, dichloromethane, acetone, chloroform and the like.
Suitable plastisizer may be one or more selected from a group comprising dibutyl sebacate, diethyl phthalate, triethyl citrate, tibutyl citrate, triacetin, acetylated monoglycerides, phthalate esters, castor oil and the like.
Suitable anti-tacking agent may be one or more selected from a group comprising adipic acid, magnesium stearate, calcium stearate, zinc stearate,


hydrogenated vegetable oils, sterotex, glyceryl monostearate, talc, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate and the like.
Suitable film forming polymers may be one or more selected from a group comprising cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl alcohol phthalate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1
Table 1: Composition of the delayed release part of Controlled release diltiazem
pharmaceutical composition

Ingredient % w/w
First Drug Layering Diltiazem HCI 24.87
HPMC/ Povidone 3.22
Talc 2.53
P.Water q.s.
NPS 8.98
Internal coating Eudragit RS 30D 13.93
Triethyl citrate 2.19
Dibutyl sebacate/ Acetyltributyl citrate 0.58
Talc 6.33
Glyceryl monostearate 0.69
P. Water q.s.
Protective coating Eudragit L30 D55 2.65
TEC 0.26
Talc 0.26


P. Water q.s.
Second Drug Layering Diltiazem HCI 10.36
HPMC 1.38
Talc 1.15
P. Water q.s.
External coating Eudragit RS 30D 6.79
Triethyl citrate 1.09
Dibutyl sebacate/ Acetyltributyl citrate 0.26
Talc 3.05
Glyceryl monostearate 0.35
P.Water q.s.
Table 2: Composition of the rapid release part of controlled release diltiazem
pharmaceutical composition

Sr. No. Ingredient % w/w
Intragranular Diltiazem HCI 42.00
HPMC 35.00
Ethyl cellulose 12.00
Microcrystalline Cellulose 6.67
Povidone K90 3.33
I PA q.s.
P. Water q.s.
Extragranular Magnesium stearate 1.00
Total 100.00
Procedure:
Delayed Release Part: Accurately weigh diltiazem, hydroxypropylmethyl cellulose and talc. Disperse these components in water to form a suspension. This suspension is applied on the NPS using Wruster coater. After this coating, the pellets are sized to get uniform size pellets. Eudragit, triethyl citrate and dibutyl sebacate are accurately weighed and mixed together. Added glyceryl monostearate in water and homogenized after heating to 65°C, followed by the


addition of talc and then the blend of eudragit triethyl citrate and dibutyl sebacate. The suspension so formed is applied as a coating on the inert core bearing drug layer. After polymer coating, the pellets are cured at 40°C for 24 h. for the protective coating, Eudragit, TEC and talc are weighed accurately and mixed in water to form a suspension. This suspension is homogenized by stirring and then applied on the core bearing drug layer and extended release coating. After applying the protective coating, the pellets are again dried in an oven. The dried pellets are again coated with a suspension of diltiazem, HPMC and talc in water followed by drying and then finally coating again with the external coating, the external coating comprises a suspension of Eudragit, Triethyl citrate, Dibutyl sebacate, Glyceryl monostearate and Talc in water. The pellets so formed are dried and sized to get uniform size pellets.
Rapid Release Part: Accurately weighed amounts of diltiazem, HPMC, ethyl cellulose and microcrystalline cellulose are sifted through suitable size sieve and mixed. Accurately weighed amount of povidone is dissolved in a mixture of isopropyl alcohol and water. The blend of diltiazem, HPMC, ethyl cellulose and microcrystalline cellulose is granulated using the solution of povidone. The granules so obtained are dried and passed through suitable size sieve. The sized granules are mixed with accurately weighed and sifted magnesium stearate. This blend is compressed to tablets using appropriate tooling.
Controlled release pharmaceutical composition: 10-50% of the rapid release part and 10-90% of delayed release part is filled in the hard gelatin capsules.


WE CLAIM:
1. A controlled release diltiazem pharmaceutical composition comprising:
a) delayed release part comprising an inert core which having the following sequence of coatings i) a drug layering ii) an extended release coating iii) optionally a protective coating, iv) second drug layering and v) external coating,
b) rapid release part comprising tablets of diltiazem wherein the said tablets comprise diltiazem or salts thereof and rate controlling agent.

2. The controlled release diltiazem pharmaceutical composition according to claim 1 wherein said controlled release diltiazem pharmaceutical comprises a blend of delayed release part and rapid release part in a ration varying between 1:100 and 100:1.
3. The controlled release diltiazem pharmaceutical composition according to claim 1 wherein said controlled release diltiazem pharmaceutical composition exhibits the following in-vitro dissolution pattern when measured in a type 2 dissolution apparatus (paddle) in 900 ml of 0.1 N HCI at 100 rpm: a) from 0-30% of total diltiazem is released after 6 hours; b) from 10-50% of total diltiazem is released after 12 hours; c) from 20-70% of total diltiazem is released after 18 hours; d) not less than 55% of total diltiazem is released after 24 hours; and e) not less than 75% of total diltiazem is released after 30 hours.
4. The controlled release diltiazem pharmaceutical composition according to claim 1 wherein delayed release part exhibits an in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) in 900 ml of 0.1N HCI at 100 rpm: a) from 0-50% of diltiazem is released after 12 hours; b) not less than 50% of diltiazem is released after 18 hours; and e) not less than 85% of total diltiazem is released after 30 hours.


5. The controlled release diltiazem pharmaceutical composition according to claim 1 wherein rapid release part exhibits an in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) in 900 ml of 0.1N HCI at 100 rpm: a) from 0-50% of diltiazem is released after 2 hours; b) not less than 80% of diltiazem is released after 6 hours; and e) not less than 85% of total diltiazem is released after 8 hours.
6. The controlled release diltiazem pharmaceutical composition according to claim 1 wherein diltiazem or salts thereof comprises diltiazem hydrochloride.
7. The controlled release diltiazem pharmaceutical composition according to claim 1 wherein diltiazem hydrochloride is present in the range between 100 mg and 600 mg.
8. The controlled release diltiazem pharmaceutical composition according to claim 1 wherein rate controlling agent comprises one or more carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers, natural or synthetic waxes, fatty acids, fatty alcohols, fatty acid esters, fatty acid glycerides and mixtures thereof.
9. The controlled release diltiazem pharmaceutical compositions according to claim 1, the pharmaceutically acceptable excipients are fillers, binders, disintegrants, lubricants, glidants, plastisizer, anti-tacking agent, aqueous or non-aqueous solvents, film forming polymers and the like.