FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10 and Rule 13]
SUSTAINED RELEASE COMPOSITIONS OF
RANOLAZINE AND PROCESS FOR
PREPARATION THEREOF

Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009, Gujarat,
India

The following specification particularly 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 sustained release pharmaceutical compositions of ranolazine; and process for preparing such compositions.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,567,264 discloses ranolazine, (±)-N-(2, 6-dimethylphenyl)-4-[2-
hydroxy-3-(2-methoxyphenoxy)-propyl]-1 -piperazineacetamide, and its
pharmaceuticaly acceptable salts, and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise-induced angina, and myocardial infarction.
The presently preferred route of administration for ranolazine and its pharmaceuticaly acceptable salts and esters is oral. A typical oral dosage form is a compressed tablet, a hard gelatin capsule filled with a powder mix or granulate, or a soft gelatin capsule (softgel) filled with a solution or suspension. U.S. Pat. No. 5,472,707 discloses a high-dose oral formulation employing super-cooled liquid ranolazine as a fill solution for a hard gelatin capsule or softgel. One problem with conventional oral dosage formulations is that they are not ideally suited to ranolazine and its pharmaceutically acceptable salts, because the solubility of ranolazine is relatively high at the low pH that occurs in the stomach. Furthermore ranolazine also has a relatively short plasma half-life. The high acid solubility property of ranolazine results in rapid drug absorption and clearance, causing large and undesirable fluctuations in plasma concentration of ranolazine and a short duration of action, thus necessitating frequent oral administration for adequate treatment.
U.S. Pat. No. 6,303,607 discloses a pharmaceutical dosage form comprising at least about 50 wt % ranolazine and at least one pH-dependent binder that inhibits the release of ranolazine from the sustained release dosage form when the sustained release dosage form is subjected to an aqueous environment having a pH of the stomach and that promotes the release of a therapeutic amount of ranolazine in an aqueous solution having a pH above about 4.5.
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U.S. Pat. No. 6,369,062 discloses a sustained release tablet of ranolazine comprising a pH-dependent binder. The pH-dependent binders suitable for use in this invention are those which inhibit rapid release of drug from a tablet during its residence in the stomach (where the pH is-below about 4.5), and which promotes the release of a therapeutic amount of ranolazine from the dosage form in the lower gastrointestinal tract (where the pH is generally greater than about 4.5). The most preferred pH-dependent binder is methacrylic acid copolymer. Sustained release tablets of ranolazine sold under the trade name RANEXA® by Gilead are believed to be based on the teachings of U.S. Pat. No. 6,369,062.
There remains a need in the art for alternative sustained release pharmaceutical compositions of ranolazine. We have surprisingly found out that sustained release composition of ranolazine can also be achieved without using any pH-dependent binder.
SUMMARY OF THE INVENTION
In one aspect, the specification discloses a sustained release pharmaceutical composition comprising:
(i) ranolazine;
(ii) one or more rate controlling polymer; and
(iii) optionally one or more pharmaceuticaly acceptable excipients.
In yet another aspect, the specification discloses a process for preparation of a sustained release pharmaceutical composition, wherein the process comprises:
(i) mixing ranolazine and optionally one or more pharmaceuticaly acceptable
excipients; (ii) granulating the mixture of step (i) with a solution/dispersion of one or more
rate controlling polymer; (iii) drying the granules of step (ii);
(iv) mixing the granules of step (iii) with a rate controlling polymer and optionally one or more pharmaceuticaly acceptable excipients and;
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(v) compressing the mixture of step (iv) into a tablet; and
(vi) optionally coating the product of step (v) with a film coating agent.
In still another aspect, the specification discloses a process for preparation of a sustained release pharmaceutical composition, wherein the process comprises:
(i) mixing ranolazine and optionally one or more pharmaceutically acceptable
excipients; (ii) granulating the mixture of step (i) with a solution/dispersion of one or more
hydrophobic rate controlling polymer; (iii) drying the granules of step (ii); (iv) mixing the granules of step (iii) with a hydrophilic rate controlling polymer
and optionally one or more pharmaceutically acceptable excipients and; (v) compressing the mixture of step (iv) into a tablet; and (vi) optionally coating the product of step (v) with a film coating agent.
DETAILED DESCRIPTION OF THE INVENTION
The term "ranolazine" as used herein refers to ranolazine free base or pharmaceutically acceptable salts thereof. It also includes enantiomers, hydrates, solvates and polymorphs of the free base or pharmaceutically acceptable salts thereof; or mixtures thereof. Ranolazine may be present in an amount ranging from 10 to 80 % by weight of the composition, preferably in a range of 20 to 70 % by weight of the composition, more preferably in a range of 25 to 70 % by weight of the composition.
In one embodiment, it discloses the sustained release pharmaceutical composition comprising ranolazine; one or more rate controlling polymer; and optionally one or more pharmaceutically acceptable excipients.
The term "rate controlling polymer" as used herein and appended claims refers to a hydrophilic polymer, hydrophobic polymer or a mixture thereof. Suitable hydrophilic
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polymers may be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl ethylcellulose, methyl cellulose, carboxymethylcellulose, carbopol, polyethylene oxide, polyvinylpyrrolidone, sodium alginate, xanthan gum, carrageenan, polyvinyl alcohol, locust bean gum, alginic acid or mixtures thereof. Suitable hydrophobic polymer is selected from a natural fat as such or totally or partially hydrogenated, beeswax, a mono-, bi- or tri-substituted glyceride, glyceryl palmitostearate, glyceryl behenate, diethyleneglyco) palmitostearate, a polyethyleneglycol stearate, a polyoxyethyleneglycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, polyethyleneglycol palmitostearate, mono- or di-glyceryl behenate, a fatty alcohol associated with a polyethoxylate fatty alcohol, cetyl alcohol, stearic acid, a saturated or unsaturated fatty acid or a hydrogenated derivative thereof, hydrogenated castor oil, ethyl cellulose or mixtures thereof. The rate controlling polymer may be present intragranularly, extragranularly or both. The rate controlling polymer provides the sustained release of ranolazine for a period of more than 12 hours, preferably 24 hours. Preferably, rate controlling polymer comprises a mixture of hydrophilic and a hydrophobic polymer.
The hydrophobic rate controlling polymer may be present in an amount ranging from 1-30 % by weight of the composition, preferably 2-20 % by weight of the composition and more preferably 3-10 % by weight of the composition.
The hydrophilic rate controlling polymer may be present in an amount ranging from 1-50 % by weight of the composition, preferably 3-40 % by weight of the composition and more preferably 5-30 % by weight of the composition.
The pharmaceutical compositions as described herein may comprise one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, lubricant, glidant, surfactant, anti-oxidant, anti-tacking agent, binder and plasticizer.
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Diluent as described herein may be selected from powdered cellulose, microcrystalline cellulose, starch, sugars such as lactose, sucrose, dextrose, dextrin, and the like; sugar alcohols such as mannitol, sorbitol or erythritol; calcium phosphate, calcium carbonate, calcium sulphate; and mixtures thereof. The diluent may be present in an amount ranging from 1 % to 50 % by weight of the composition.
Disintegrant as described herein may be selected from carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium alginate, starch, and the like. The disintegrant may be present in an amount ranging from 1 % to 10 % by weight of the composition.
Lubricant and/or glidant may be selected from talc, magnesium stearate, calcium stearate, colloidal silicon oxide, finely divided silicon oxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, sodium stearyl fumarate, magnesium trisilicate; and mixtures thereof. The lubricant and/or glidant may be present in an amount ranging from 0.1 to 3 % by weight of the composition.
Surfactant as described herein may be selected from one or more of non-ionic and ionic (i. e., cationic, anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions. Suitable surfactants include mono fatty acid esters of polyoxyethylene sorbitan such as those sold under the brand name Tween®; sodium lauryl sulfate, polyoxyethylene castor oil derivatives such as those sold under the brand name Cremophor®, polyethoxylated fatty acids and their derivatives, propylene glycol fatty acid esters, sterol and sterol derivatives; sorbitan fatty acid esters and their derivatives, sugar esters, polyoxyethylene-polyoxypropylene block copolymers such as those sold under the brand name Poloxamer®, soy lecithin, sodium stearyl
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fumarate, and mixtures thereof. The surfactant may be present in an amount ranging from 0.01 % to 5 % by weight of the composition.
Anti-oxidant as described herein may be selected from butylated hydroxanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, ascorbic acid; and mixtures thereof. The anti-oxidant may be present in an amount ranging from 0.01 to 5 % by weight of the composition.
Anti-tacking agent as described herein may be selected from talc, colloidal silicon dioxide, finely divided silicon dioxide, glyceryl monostearate, and the like. The anti-tacking agent may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, gelatin, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. The binder may be present in an amount ranging from 0.1 % to 8 % by weight of the composition.
Plasticizer as described herein may be selected from propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate; or mixtures thereof. The plasticizer may be present in an amount ranging from 0.01 % to 10 % by weight of the composition.
The pharmaceutical compositions as described herein may be prepared by techniques such as granulation. For example, ranolazine may be mixed with pharmaceutically acceptable excipients selected form diluent, binder, one or more rate controlling polymer and disintegrant, and the mixture may be granulated with water or an organic solvent or mixture thereof, in an apparatus such as rapid mixer granulator or a fluid bed processor, to form granules. Alternatively, the rate controlling polymer or mixture thereof may be dissolved or dispersed or suspended
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in water or an organic solvent or mixture thereof and the solution/dispersion may be used to granulate ranolazine optionally mixed with other pharmaceutically acceptable excipients selected form diluent, binder and disintegrant. The granules may be dried, sized, mixed with one or more excipients such as a diluent, disintegrant, lubricant, glidant, anti-oxidant, surfactant and a rate controlling polymer, and compressed into tablets. The tablet may optionally be coated with a film forming agent.
In one embodiment, a sustained release tablet is prepared by:
mixing ranolazine with one or more pharmaceutically acceptable excipients,
granulating the mixture with a solution/dispersion of one or more rate
controlling polymer,
drying the granules,
mixing the granules with a rate controlling polymer, and one or more
pharmaceutically acceptable excipients,
compressing the mixture into a tablet, and
optionally coating the tablet with film forming agent.
In another embodiment, a sustained release tablet is prepared by:
mixing ranolazine with one or more pharmaceutically acceptable excipients,
granulating the mixture with a solution/dispersion of one or more hydrophobic
rate controlling polymer,
drying the granules,
mixing the granules with a hydrophilic rate controlling polymer and optionally
one or more pharmaceutically acceptable excipients;
compressing the mixture into a tablet, and
optionally coating the tablet with film forming agent.
The pharmaceutical composition as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
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EXAMPLES 1 - 2

Ingredients Amount / Tab (in mg)
Example 1 Example 2
Ranolazine 1002.20 1002.20
PVP K 30 25.0 25.0
Microcrystalline cellulose 22.8 22.8
Aquacoat ECD 30D 333.40 333.40
Carrageenan A 200.0 220.0
Lactose Monohydrate 70.0 60.0
Microcrystalline cellulose 175.0 165.0
PVP K30 25.0 25.0
Magnesium Stearate 30.0 30.0
Opadry II 48.80 48.80
Ferric Oxide Yellow 0.74 0.74
Water q.s. q.s.
Total weight 1669.54 1699.54
PROCEDURE: Ranolazine, PVP K 30 and microcrystalline cellulose were sifted and mixed. The powder was granulated with aquacoat ECD 30 D. The granules were dried and sized. The granules were mixed with Carrageenan A, lactose, microcrystalline cellulose and PVP K 30. The mixture was lubricated by addition of magnesium stearate and compressed into tablets. Tablets were coated with an aqueous solution of ferric oxide and Opadry II.
EXAMPLE 3

Ingredients Amount / Tab (in mg)
Ranolazine 1000.0
Microcrystalline cellulose 25.0
Carrageenan A 415.0
PVP K30 30.0
Lactose 100.0
Magnesium stearate 30.0
IPA q.s.
Total weight 1600.00

PROCEDURE: Ranolazine, microcrystalline cellulose and Carrageenan were sifted and mixed. The powder was granulated using alcoholic dispersion of PVP K30. The granules were dried and sized. The granules were mixed with lactose and magnesium stearate and the mixture was compressed into tablets.
The dissolution profile of Examples 1 & 2 in comparison with the marketed ranolazine sustained release tablet (Ranexa ®) is depicted in Table 1.
Table-1: Dissolution profile of Examples 1 & 2 in USP Type II Apparatus (paddle with sinkers), 50 rpm, at 37 ± 0.5 °C

Time (h) Ranexa ® Example 1 Example 2
0 0.0 0.0 0.0
0.5 12.7 18.7 12.4
1 19.3 22.5 15.2
2 27.6 32.1 22.8
4 39.0 43.8 38.0
6 47.8 51.8 45.6
8 54.5 60.4 50.2
10 60.2 64.2 52.1
12 64.1 68.2 58.1
16 71.3 77.2 64.5
20 77.5 84.5 66.4
24 81.7 89.2 69.4
[Dissolution media: 0.1 N HCI (OGD)]
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WE CLAIM:
1. A sustained release pharmaceutical composition comprising:
(i) ranolazine;
(ii) one or more rate controlling polymer; and
(iii) optionally one or more pharmaceutically acceptable excipients.
2. The composition of claim 1, wherein rate controlling polymer is selected from a
hydrophilic polymer, a hydrophobic polymer or mixture thereof.
3. The composition of claim 1, wherein hydrophilic rate controlling polymer is
selected from a group consisting of hydroxypropyl methylcellulose, hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropyl ethylcellulose, methyl cellulose,
carboxymethylcellulose, carbopol, polyethylene oxide, polyvinylpyrrolidone,
sodium alginate, xanthan gum, carrageenan, polyvinyl alcohol, locust bean gum,
alginic acid or mixtures thereof.
4. The composition of claim 1, wherein hydrophobic rate controlling polymer is selected from a group consisting of natural fat as such or totally or partially hydrogenated, beeswax, a mono-, bi- or tri-substituted glyceride, glyceryl palmitostearate, glyceryl behenate, diethyleneglycol palmitostearate, a polyethyleneglycol stearate, a polyoxyethyleneglycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, polyethyleneglycol palmitostearate, mono-or di-glyceryl behenate, a fatty alcohol associated with a polyethoxylate fatty alcohol, cetyl alcohol, stearic acid, a saturated or unsaturated fatty acid or a hydrogenated derivative thereof, hydrogenated castor oil, ethyl cellulose or mixtures thereof.
5. The composition of claim 1, wherein the rate controlling polymer is present intragranularly, extragranularly or both intragranularly and extragranularly.
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6. The composition of claim 1, wherein the hydrophobic rate controlling polymer may be present in an amount ranging from 1-30 % by weight of the composition, preferably 2-20 % by weight of the composition and more preferably 3-10 % by weight of the composition.
7. The composition of claim 1, wherein the hydrophilic rate controlling polymer may be present in an amount ranging from 1-50 % by weight of the composition, preferably 3-40 % by weight of the composition and more preferably 5-30 % by weight of the composition.
8. The composition of claim 1, wherein the composition further comprises a pharmaceuticaly acceptable excipient selected form a group consisting of diluent, disintegrant, lubricant, glidant, surfactant, anti-oxidant, anti-tacking agent, binder and plasticizer.
9. A process for preparation of a sustained release pharmaceutical composition,
wherein the process comprises:
(i) mixing ranolazine and optionally one or more pharmaceutically acceptable
excipients; (ii) granulating the mixture of step (i) with a solution/dispersion of one or more
rate controlling polymer; (iii) drying the granules of step (ii); (iv) mixing the granules of step (iii) with a rate controlling polymer and
optionally one or more pharmaceutically acceptable excipients and; (v) compressing the mixture of step (iv) into a tablet; and (vi) optionally coating the product of step (v) with a film coating agent.
10. A process for preparation of a sustained release pharmaceutical composition,
wherein the process comprises:
(i) mixing ranolazine and optionally one or more pharmaceutically acceptable excipients;
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(ii) granulating the mixture of step (i) with a solution/dispersion of one or more
hydrophobic rate controlling polymer; (iii) drying the granules of step (ii); (iv) mixing the granules of step (iii) with a hydrophilic rate controlling polymer
and optionally one or more pharmaceutically acceptable excipients; (v) compressing the mixture of step (iv) into a tablet; and (vi) optionally coating the product of step (v) with a film coating agent.
Dated this 19th day of September, 2009
For Torrent Pharmaceuticals Ltd., Praveen Chand Gandhi
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