FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
STABLE PHARMACEUTICAL
COMPOSITIONS OF HMG-CoA
REDUCTASE INHIBITOR 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
fhe following specification describes the invention:
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FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical compositions of HMG-CoA reductase inhibitor and process for preparation thereof. More particularly, it relates to pharmaceutical compositions of HMG-CoA reductase inhibitor comprising polyethylene glycol (PEG), alone or in combination with sodium lauryl sulphate (SLS); and process for preparing such compositions.
BACKGROUND OF THE INVENTION
Atorvastatin, lovastatin, pravastatin, simvastatin, mevastatin, fluvastatin and cerivastatin, derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents.
Atorvastatin and pharmaceutical^ acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase enzyme and are potent lipid-lowering compounds useful as hypolipidemic and/or hypocholesterolemic agents. The currently marketed composition of atorvastatin sold by Pfizer under the brand name Lipitor® comprise atorvastatin calcium, which is disclosed in US 5,273,995 and has the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-.p,S-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1).
Atorvastatin can exist in crystalline and amorphous forms. Crystalline forms of atorvastatin calcium are disclosed in US 5,969,156, US 6,121,461 and US 6,605,729. Additionally, a number of published international patent applications have disclosed various crystalline forms of atorvastatin as well as process for preparing amorphous atorvastatin. These include: WO 00/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO 02/41834; WO 02/43667; WO 02/43732; WO 02/051804; WO 02/057228; WO 02/057229; WO 02/057274; WO 02/059087; WO 02/083637; WO 02/083638; WO 03/011826; WO 03/050085; WO 03/070702 and WO 04/022053.
Atorvastatin is particularly sensitive to an acidic environment in which hydroxy acids are degraded into a lactone. Atorvastatin may also be degraded by
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environmental factors such as temperature, moisture, low pH or carbon dioxide from the air and light. While formulating compositions of atorvastatin, its degradation may also be accelerated by interactions with other pharmaceutical excipients, such as diluents, binders, lubricants, glidants and disintegrating agents. Various approaches are disclosed in the art to provide stable compositions of atorvastatin wherein degradation of atorvastatin is minimized.
US 5,686,104 and US 6,126,971 disclose solid oral compositions of atorvastatin wherein pharmaceutically acceptable salt of atorvastatin is stabilized by addition of an alkaline earth metal salt. In one of the preferred embodiments, the compositions are prepared by wet granulation using aqueous solution of a surfactant.
US 2004/247673 discloses wet granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof with less than about 5 weight % of an alkaline earth metal salt additive and methods for preparing such compositions.
US 6,680,341 discloses stable solid pharmaceutical formulation containing a HMG-CoA reductase inhibitor and a buffering agent wherein the formulation is capable of providing a pH below 9. The patent specifically relates to process for preparation of stable active substance containing a HMG-CoA reductase inhibitor and a low amount of a buffering agent.
There remains a need in the art for alternative pharmaceutical compositions of amorphous atorvastatin having minimal degradation of atorvastatin and low level of impurities. We have surprisingly found that stable pharmaceutical compositions of atorvastatin can be prepared by using polyethylene glycol, alone or in combination with sodium lauryl sulphate.
SUMMARY OF THE INVENTION
One embodiment discloses a stable pharmaceutical composition comprising (i) an HMG-CoA reductase inhibitor,
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(ii) 0.5 % to 25 % by weight of polyethylene glycol (PEG),
(iii) optionally 0.1 % to 5 % by weight of sodium lauryl sulphate; and
(iv) at least one pharmaceutical^ acceptable excipient.
Another embodiment discloses a stable pharmaceutical composition comprising (i) atorvastatin,
(ii) 0.5 % to 25 % by weight of polyethylene glycol (PEG), (iii) optionally 0.1 % to 5 % by weight of sodium lauryl sulphate; and (iv) at least one pharmaceutically acceptable excipient.
Another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises:
(i) mixing an HMG-CoA reductase inhibitor and optionally at least one
pharmaceutically acceptable excipient, (ii) granulating an HMG-CoA reductase inhibitor or mixture of step (i) with
solution of polyethylene glycol optionally containing sodium lauryl
sulphate, (iii) drying the granules obtained in step (ii), (iv) mixing the granules of step (iii) with at least one pharmaceutically
acceptable excipient, (v) optionally lubricating the mixture of step (iv); and (vi) compressing the mixture of step (iv) or (v) into tablets or filling into
capsules.
Another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises:
(i) mixing atorvastatin and optionally at least one pharmaceutically acceptable
excipient, (ii) granulating atorvastatin or mixture of step (i) with solution of polyethylene
glycol optionally containing sodium lauryl sulphate, (iii) drying the granules obtained in step (ii), (iv) mixing the granules of step (iii) with at least one pharmaceutically
acceptable excipient, (v) optionally lubricating the mixture of step (iv); and
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(vi) compressing the mixture of step (iv) or (v) into tablets or filling into capsules.
Yet another embodiment discloses a method for treating hypercholesterolemia or preventing cardiovascular diseases selected from myocardial infarction, stroke or angina, wherein the method comprises administering a patient in need thereof a stable pharmaceutical composition; wherein the composition comprises:
(i) atorvastatin,
(ii) 0.5 to 25% of polyethylene glycol by weight of atorvastatin,
(iii) optionally 0.1 to 5% of sodium lauryl sulphate by weight of atorvastatin; and
(iv) at least one pharmaceutical^ acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION
The "HMG-CoA reductase inhibitor" as described herein may be selected from atorvastatin, pravastatin, simvastatin, lovastatin, mevastatin, fluvastatin, cerivastatin, and pharmaceutically acceptable salts thereof.
The term "atorvastatin" as described herein refers to free base of atorvastatin, racemic mixture, individual enantiomer, solvate, pharmaceutically acceptable salts or mixtures thereof. The preferred salt is atorvastatin calcium. Atorvastatin may be present in crystalline form, amorphous form, or mixture thereof. Atorvastatin may be present in an amount ranging from 1 % to 50 % by weight of the composition.
The term "stable" as described herein refers to pharmaceutical composition of atorvastatin wherein there is no significant increase in known or unknown impurities of atorvastatin, when stored at a temperature of 40°C and 75% relative humidity (RH) for a period of at least one month.
Unless specified otherwise, the term "by weight polyethylene glycol" or "by weight sodium lauryl sulphate" refers to the amount of PEG or SLS on the basis of the weight of atorvastatin.
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The term "polyethylene glycol" as described herein refers to polyethylene glycols having higher molecular weight, for example more than 1000 daltons. PEG, either alone or in combination with SLS, is used in compositions as described herein. PEG may be used in an amount ranging from 0.5 % to 25% by weight of atorvastatin. SLS may be used in an amount ranging from 0.1 to 5 % by weight of atorvastatin. PEG and/or SLS may be dispersed or dissolved in water or organic solvent or mixture thereof. In one embodiment, atorvastatin or a salt thereof may be granulated with this solution by means of spraying in an apparatus like fluidized bed processor.
The pharmaceutical compositions as described herein may comprise of one or more pharmaceutical^ acceptable excipients selected from diluent, disintegrant, alkalizing agent, anti-oxidant, surfactant or glidant / lubricant. The present invention does not cover composition(s) where polyethylene glycol is used only as a part of coating.
Diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic sodium phosphate, tribasic sodium phosphate, dextrose, kaolin; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol or erythritol; or mixtures thereof. The diluent may be present in an amount ranging from 10 % to 90 % by weight of the composition.
Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and mixtures thereof. The disintegrant may be present in an amount ranging from 1 % to 15 % by weight of the composition.
Alkalizing agent may be selected from meglumine, tromethamine, sodium carbonate, sodium bicarbonate, sodium citrate, potassium citrate, dibasic sodium phosphate, tribasic sodium phosphate, hydrogen phosphate, sodium hydroxide, potassium hydroxide; and mixtures thereof. The alkalizing agent may be present
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in an amount which provides a pH of more than 6, preferably pH of more than 9 to the pharmaceutical composition.
Anti-oxidant 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 0.1 to 3% by weight of the composition. The anti-oxidant may be added with atorvastatin before granulation step or it may be added to the dried granules before compression step. Atorvastatin may be granulated with solution of antioxidant in combination with polyethylene glycol.
Surfactant 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 fumarate, and mixtures thereof. The surfactant may be present in an amount ranging from 0.1 % to 5 % by weight of the composition. Sodium lauryl sulphate when used as a stabilizer may also act as a surfactant.
Lubricant / glidant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate; and mixtures thereof. The lubricant / glidant may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
The pharmaceutical composition may be in the form of a tablet, a capsule or granules.
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One embodiment discloses a stable pharmaceutical composition comprising; (i) atorvastatin;
(ii) 0.5 % to 25 % by weight polyethylene glycol; (iii) optionally 0.1 to 5% by weight sodium lauryl sulphate; and (iv) at least one pharmaceutically acceptable excipient selected from diluent, disintegrant, alkalizing agent, anti-oxidant, surfactant or glidant/lubricant
Another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises:
(i) mixing HMG-CoA reductase inhibitor selected from atorvastatin, fluvastatin
or pravastatin and optionally at least one pharmaceutically acceptable
excipient selected from diluent, disintegrant or glidant/lubricant, (ii) granulating HMG-CoA reductase inhibitor selected from atorvastatin,
fluvastatin or pravastatin or mixture of step (i) with a solution of
polyethylene glycol optionally containing sodium lauryl sulphate, (iii) drying the granules obtained in step (ii), (iv) mixing the granules of step (iii) with at least one pharmaceutically
acceptable excipient selected from diluent, disintegrant, alkalizing agent,
anti-oxidant, surfactant or glidant/lubricant, (v) optionally lubricating the mixture of step (iv); and (vi) compressing the mixture of step (iv) or (v) into tablets or filling into
capsules.
Another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises:
(i) mixing HMG-CoA reductase inhibitor selected from atorvastatin, fluvastatin
or pravastatin and an anti-oxidant, (ii) granulating mixture of step (i) with a solution of polyethylene glycol
optionally containing sodium lauryl sulphate, (iii) drying the granules obtained in step (ii), (iv) mixing the granules of step (iii) with at least one pharmaceutically
acceptable excipient selected from diluent, disintegrant, alkalizing agent,
anti-oxidant, surfactant or glidant/lubricant,
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(v) optionally lubricating the mixture of step (iv); and (vi) compressing the mixture of step (iv) or (v) into tablets or filling into capsules.
Yet another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises:
(i) mixing HMG-CoA reductase inhibitor selected from atorvastatin, fluvastatin
or pravastatin and optionally at least one pharmaceutically acceptable
excipient selected from diluent, disintegrant orglidant/lubricant, (ii) granulating mixture of step (i) with a solution of anti-oxidant and
polyethylene glycol, (iii) drying the granules obtained in step (ii), (iv) mixing the granules of step (iii) with at least one pharmaceutically
acceptable excipient selected from diluent, disintegrant, alkalizing agent,
anti-oxidant, surfactant or glidant/lubricant, (v) optionally lubricating the mixture of step (iv); and (vi) compressing the mixture of step (iv) or (v) into tablets or filling into
capsules.
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
EXAMPLE 1

Sr. No Ingredient Quantity (mg/tablet)
1 Atorvastatin Calcium 82.87
2 Lactose 750.00
3 Microcrystalline cellulose 241.13
4 Polyethylene glycol 4.00
5 Crospovidone 90.00
6 Sodium carbonate 20.00
7 Magnesium Stearate 12.00
8 Purified water q.s.
9 HPMC6cps 13.34
10 Titanium dioxide 5.33
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11 Talc 3.33
12 Polyethylene glycol 2.00
13 Isopropyl alcohol + methylene chloride (1:1) q.s.
PROCEDURE: Atorvastatin and a portion of lactose anhydrous were mixed together and granulated with aqueous solution of polyethylene glycol by top spray in fluidized bed processor and the granules were dried. In a separate batch, remaining quantity of lactose and a portion of microcrystalline cellulose were mixed together and granulated with aqueous solution of sodium carbonate by top spray in fluidized bed processor and the granules were dried. The granules obtained above were mixed with remaining quantity of microcrystalline cellulose and crospovidone; the mixture was lubricated by addition of magnesium stearate and compressed into tablets. The tablets were coated by dispersion of hydroxypropyl methylcellulose, talc, polyethylene glycol 6000 and titanium dioxide in a mixture of isopropyl alcohol and methylene chloride.
EXAMPLE 2

Sr. No Ingredient Quantity (mg/tablet)
1 Atorvastatin Calcium 82.87
2 Lactose anhydrous 750.00
3 Microcrystalline cellulose 240.13
4 Sodium lauryl sulphate 1.00
5 Polyethylene glycol 4.00
6 Crospovidone 90.00
7 Sodium carbonate 20.00
8 Magnesium Stearate 12.00
9 Purified water q.s.
10 HPMC 6 cps 13.34
11 Titanium dioxide 5.33
12 Talc 3.33
13 Polyethylene glycol 6000 2.00
14 Isopropyl alcohol + methylene chloride (1:1) q.s.
PROCEDURE: Atorvastatin and a portion of lactose anhydrous were mixed together and granulated with aqueous solution of sodium lauryl sulphate and polyethylene glycol by top spray in fluidized bed processor and the granules were
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dried. In a separate batch, remaining quantity of lactose and a portion of microcrystalline cellulose were mixed and granulated with aqueous solution of sodium carbonate by top spray in fluidized bed processor and the granules were dried. The granules obtained above were mixed with remaining quantity of microcrystalline cellulose and crospovidone; the mixture was lubricated by addition of magnesium stearate and compressed into tablets. The tablets were coated by dispersion of hydroxypropyl methylcellulose, talc, polyethylene glycol 6000 and titanium dioxide in a mixture of isopropyl alcohol and methylene chloride.
EXAMPLE 3

Sr No Ingredients Qty/tab (mg)
1 Atorvastatin Calcium 82.87
2 Lactose Monohydrate 750.00
3 Butylated hydroxyl anisole 0.24
4 Polyethylene glycol 6.00
5 Methylene dichloride q.s.
6 Microcrystalline cellulose 240.89
7 Sodium Carbonate 15.00
8 Purified water q.s.
9 Crospovidone 90.00
10 Poloxamer 3.00
11 Methanol q.s.
12 Magnesium Stearate 12.00
13 HPMC6cps 14.40
14 Titanium dioxide 4.32
15 Talc 2.40
16 Polyethylene glycol 6000 2.88
17 Isopropyl alcohol + Methylene chloride (1:1) q.s.
PROCEDURE: Atorvastatin and a portion of lactose anhydrous were mixed together and granulated with solution of sodium lauryl sulphate and polyethylene glycol in methylene dichloride by top spray in fluidized bed processor and the granules were dried. In a separate batch, remaining quantity of lactose and a portion of microcrystalline cellulose were mixed and granulated with aqueous solution of sodium carbonate by top spray in fluidized bed processor and the
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granules were dried. The granules were again sprayed with solution of poloxamer in methanol and dried. The granules obtained above were mixed with remaining quantity of microcrystalline cellulose and crospovidone; the mixture was lubricated by addition of magnesium stearate and compressed into tablets. The tablets were coated by dispersion of hydroxypropyl methylcellulose, talc, polyethylene glycol 6000 and titanium dioxide in a mixture of isopropyl alcohol and methylene chloride.
EXAMPLE 4

Sr. No Ingredient
1 Fluvastatin
2 Lactose anhydrous
3 Microcrystalline cellulose
4 Sodium lauryl sulphate
5 Polyethylene glycol
6 Crospovidone
7 Tromethamine
8 Magnesium Stearate
9 Purified water
10 HPMC 6 cps
11 Titanium dioxide
12 Talc
13 Polyethylene glycol 6000
14 Isopropyl alcohol + methylene chloride (1:1)
PROCEDURE: The composition may be prepared by the process as described in Example 2.
EXAMPLE 5

Sr. No Ingredient
1 Pravastatin sodium
2 Lactose
3 Microcrystalline cellulose
4 Polyethylene glycol
5 Crospovidone
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6 Meglumine
7 Magnesium Stearate
8 Purified water
9 HPMC 6 cps
10 Titanium dioxide
11 Talc
12 Polyethylene glycol
13 Isopropyl alcohol + methylene chloride (1:1)
PROCEDURE: The composition may be prepared by the process as described in Example 1.
Dated This 23rd Day of March, 2007

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ABSTRACT
The present invention relates to stable pharmaceutical compositions of HMG-CoA reductase inhibitor and process for preparation thereof. More particularly, it relates to pharmaceutical compositions of HMG-CoA reductase inhibitor comprising of polyethylene glycol, alone or in combination with sodium lauryl sulphate; and process for preparing such compositions.