FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
STABLE PHARMACEUTICAL
COMPOSITIONS OF ATORVASTATIN
AND AMLODIPINE


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

The following specification describes the invention:

3 1 JUL 2008

FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical compositions of atorvastatin and amlodipine, and process for preparation thereof.
BACKGROUND OF THE INVENTION
Atorvastatin and pharmaceutically 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 is chemical known as [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbony|]-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, all assigned to Warner-Lambert. 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 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.
Amlodipine, a calcium channel blocker, and its salts are disclosed in U.S. Patent No. 4,572,909. Further, the besylate salt of amlodipine is disclosed in U.S. Patent No. 4,879,303. It is known that amlodipine is hygroscopic in nature and may
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degrade in presence of moisture. One of the major routes of degradation is known to be pH-dependent catalytic oxidative process. One of the major related substance produced by degradation is 3-ethyl-5-methyl 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methylpyridine-3, 5-dicarboxylate ("Impurity D" of Formula (I)), which is typically a cause of concern with respect to stability of amlodipine formulation.

Amlodipine Impurity D (I)
Hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease, ultimately resulting in adverse cardiac events. This clustering of risk factors is potentially due to a common mechanism. It would therefore be advantageous for patients to have a single therapy which treats both of these conditions. The combination of atorvastatin calcium and amlodipine besylate is marketed as tablets by Pfizer in the USA under the name of Caduet® The PCT application WO 99/11259, assigned to Warner-Lambert, discloses additive and synergistic combinations of amlodipine and atorvastatin whereby those combinations are useful in treating subjects suffering from angina pectoris, atherosclerosis and combined hypertension and hyperlipidemia.
The PCT application WO 03/11283, assigned to Warner-Lambert, discloses a pharmaceutical composition comprising two components: (a) one component comprising a granulation of atorvastatin or pharmaceutically acceptable salts thereof and a carrier including an alkalizing agent that forms a pH greater than 5; and (b) a second component comprising amlodipine or pharmaceutically acceptable salts thereof and a carrier excluding an alkalizing agent that forms a pH greater than 5, wherein the two components are combined to form a final composition for a solid dosage form.
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The PCT application WO 2006/070248, assigned to Ranbaxy, discloses a process for making a pharmaceutical composition comprising amlodipine and atorvastatin or pharmaceutically acceptable salts thereof, wherein the process comprises the steps of preparing a blend or granules of atorvastatin; preparing a blend or granulation of amlodipine; mixing the blends or granules; lubricating the mixture and compressing the lubricated mixture to form tablets or filling into a capsule.
There remains a need in the art for alternative pharmaceutical compositions of atorvastatin and amlodipine having minimal degradation of both active ingredients and low level of impurities. We have surprisingly found that stable pharmaceutical compositions of atorvastatin and amlodipine can be prepared, wherein both the active ingredients are not in direct contact with each other.
SUMMARY OF THE INVENTION
One embodiment provides a stable pharmaceutical composition comprising:
(i) a first component comprising atorvastatin, an alkalizing agent and at
least one pharmaceutically acceptable excipient; and (ii) a second component comprising amlodipine, an alkalizing agent and at
least one pharmaceutically acceptable excipient.
Another embodiment provides a process for preparing a stable composition comprising the steps of:
(i) preparing a first component comprising atorvastatin, an alkalizing
agent and at least one pharmaceutically acceptable excipient; (ii) preparing a second component comprising amlodipine, an alkalizing
agent and at least one pharmaceutically acceptable excipient; (iii) compressing the first component and the second component into a bilayer tablet.
Another embodiment provides a process for preparing a stable composition comprising the steps of:
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(i) preparing a first component comprising atorvastatin, an alkalizing
agent and at least one pharmaceutically acceptable excipient;
(ii) preparing a second component comprising amlodipine, an alkalizing agent and at least one pharmaceutically acceptable excipient;
(iii) mixing the first component and the second component;
(iv) optionally lubricating the mixture of step (iii); and
(v) compressing the mixture of step (iii) or step (iv) into a tablet.
DETAILED DESCRIPTION OF THE INVENTION
The term "atorvastatin" as described herein refers to free base of atorvastatin as well as pharmaceutically acceptable salts thereof. It also includes racemic mixture, enantiomer, hydrate and solvate of the base or pharmaceutically acceptable salts thereof; or mixtures thereof. The preferred salt is atorvastatin calcium. Atorvastatin may be present in crystalline form, amorphous form, or mixture thereof. In a preferred embodiment, atorvastatin is amorphous atorvastatin calcium. Atorvastatin may be present in an amount ranging from 1 % to 50 % by weight of the composition.
The term "amlodipine" as used herein includes amlodipine free base, or pharmaceutically acceptable acid addition salts thereof or mixtures thereof. It also covers anhydrous form, hydrous form, different crystalline forms, amorphous form, enantiomers of amlodipine or pharmaceutically acceptable acid addition salts thereof or mixtures thereof. Amlodipine may be present in an amount ranging from 0.1 % to 25 % by weight of the composition.
The term "stable" as described herein refers to pharmaceutical compositions wherein there is no significant increase in known or unknown impurities of atorvastatin and no significant increase in amlodipine Impurity D, when stored at a temperature of 40 °C and 75 % relative humidity (RH) for a period of at least one month. For example, in compositions as described herein the amount of known impurities of atorvastatin and/or amlodipine impurity D is not more than 0.2 % w/w and the amount of total impurity is not more than 2% w/w after a period of one month when stored at a temperature of 40 °C and 75 % relative humidity
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(RH). Some of the known impurities of atorvastatin include: 5-(4-fluorophenyl)-1-
[2-[(2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl]ethyl]-2-isoprop yl-4-phenyl-1H-
pyrrole-3-carboxylic acid phenylamide ["lactone" impurity], (3R,5R)-7-[2-(4-
fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3, 5-
dihydroxyheptanoic acid tert-butyl ester ["tertiary butyl ester" impurity), 2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) ["atorvastatin isomer" impurity] and 3,8-dihydroxy-2-(1-methylethyl)-4,5-diphenyl-3-[(phenylamino)carbonyl]-lH-pyrro le-1-heptanoic acid, calcium salt (2:1) ["desfluoro" impurity].
The term "component" as described herein means a portion or a part of the pharmaceutical composition. The "component" may be in the form of a powder, granule, bead, pellet, spheroid, minitablet, microtablet, coating or compressed layer, or mixture thereof. The pharmaceutical composition described herein comprises a first component containing atorvastatin and a second component containing amlodipine. The pharmaceutical compositions as described herein are prepared such that amlodipine and atorvastatin are not in direct contact with each other.
The term "alkalizing agent" as describe herein refers to excipient which is capable of providing alkaline environment around the atorvastatin and/or amlodipine. Alkalizing agent may be selected from meglumine, tromethamine, sodium carbonate, sodium bicarbonate, sodium citrate, potassium citrate, dibasic sodium phosphate, tribasic sodium phosphate, sodium hydroxide, potassium hydroxide; or mixtures thereof. The alkalizing agent may be present in an amount which imparts a pH of more than 5, preferably pH of more than 9 to the pharmaceutical composition. More particularly, the alkalizing agent may be present in an amount ranging from 0.1 % to 50 % by weight of the composition.
The pharmaceutical compositions as described herein may comprise of one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, anti-oxidant, surfactant or glidant / lubricant.
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Diluent may be selected from powdered cellulose, microcrystalline cellulose, siiicified 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.
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 0.01 to 3% by weight of the composition. In compositions as described herein, the anti-oxidant may be mixed with atorvastatin before the granulation step or it may be added to the dried granules before the compression step. Alternatively, anti-oxidant may be added to the solution / dispersion of PEG which is used to granulate atorvastatin.
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
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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 as described herein may be in the form of a tablet, capsule or sachet. Tablet may be in the form of a single or multi-layered tablet such as a bilayer tablet, compression coated tablet or inlay tablet. When in the form of a multi-layer tablet, such as a bilayer tablet, it may comprise first layer of atorvastatin and a second layer of amlodipine. The pharmaceutical compositions as described herein are prepared such that atorvastatin and amlodipine are not in direct contact with each other. For example, atorvastatin and amlodipine are not mixed together in a single step to form the composition. The compositions as described herein are prepared by combining a first component comprising atorvastatin and a second component comprising amlodipine. The first or the second component may be prepared using methods such as wet granulation, dry granulation or direct compression. For example, the first and the second component may be obtained as granules which may be compressed into a tablet or filled in a capsule. A first component may be prepared by granulating the mixture of atorvastatin and excipients with a solution / dispersion of PEG in a solvent such as water or an organic solvent, wherein the solution / dispersion may also contain an antioxidant and/or a surfactant. The granulation may be achieved in a suitable apparatus such as a fluidized bed apparatus using the "top-spray" technique. The granules may be coated further with a solution / dispersion of the alkalizing agent to form the first component. Alternatively, the dried granules may be mixed with the alkalizing agent and pharmaceutically acceptable excipients such as diluent, disintegrant, glidant and lubricant to obtain the first component. The second component may be prepared by mixing amlodipine with an alkalizing agent and pharmaceutically acceptable
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excipients such as diluent, disintegrant, binder, glidant or lubricant. Alternatively, the mixture comprising amiodipine may be granulated and the granules may be mixed with the alkalizing agent and pharmaceutically acceptable excipients such as diluent, disintegrant, glidant and lubricant to obtain the second component. Alternatively, the second component comprising amiodipine may be prepared by drug layering on the inert pellets. For example, amiodipine, binder and the alkalizing agent may be dissolved in suitable solvent and may be sprayed on inert pellets of sucrose, sugar spheres or microcrystalline cellulose. The first or the second component may also be prepared by methods such as melt granulation, extrusion-spheronization, freeze-drying, spray granulation, spray drying, coating, solvent deposition, and the like.
The compositions as described herein may further be coated with a film-forming polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone, and the like. The coating may also comprise of a plasticizer such as glyceryltriacetate, dibutyl sebacate, diethylphthalate, polyethylene glycol, propylene glycol, glycerol, castor oil, copolymers of propylene oxide and ethylene oxide, or mixtures thereof. Such compositions are also available under the brand name of Opadry® or Lustreclear®, sold by Colorcon.
The pharmaceutical compositions as described herein may be useful in treatment of hypertension as well as treatment or prevention hypercholesterolemia, hyperlipidemia and prophylaxis of conditions associated with hyperlipidemia such as myocardial infarction, stroke, angina and atherosclerosis.
In one embodiment, a bilayer tablet may be prepared by: [A] preparing a first component comprising:
(i) mixing atorvastatin with at least one pharmaceutically acceptable
excipient and optionally an alkalizing agent; (ii) granulating the mixture of step (i); (iii) drying the granules obtained in step (ii);
(iv) mixing the granules of step (iii) with the alkalizing agent and at least one pharmaceutically acceptable excipient;
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(v) optionally lubricating the mixture of step (iv); [Bl preparing a second component by the steps of:
(i) mixing amlodipine with at least one pharmaceutically acceptable
excipient and an alkalizing agent;
(ii) lubricating the mixture of step (i); [C] combining the first component and the second component into a bilayer
tablet.
In another embodiment, a tablet may be prepared by:
[A] preparing a first component by the steps of:
(i) mixing atorvastatin with at least one pharmaceutically acceptable
excipient and optionally an alkalizing agent; (ii) granulating the mixture of step (i); (iii) drying the granules obtained in step (ii); (iv) mixing the granules of step (iii) with the alkalizing agent and at least
one pharmaceutically acceptable excipient; (v) optionally lubricating the mixture of step (iv);
[B] preparing a second component by the steps of:
(i) dissolving amlodipine, an alkalizing agent and a binder in appropriate
solvent; (ii) spraying the solution on inert pellets; (iii) coating the drug layered pellets with film-forming polymer;
[C] mixing the first component and the second component and compressing the
mixture into a tablet..
In another embodiment, a bilayer tablet may be prepared by:
[A] preparing a first component by the steps of:
(t) mixing atorvastatin with at least one pharmaceutically acceptable
excipient and an alkalizing agent, (ii) granulating the mixture of step (i), . (iii) optionally lubricating the mixture of step (ii);
[B] preparing a second component by the steps of:
(i) mixing amlodipine with at least one pharmaceutically acceptable
excipient and an alkalizing agent;
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(ii) lubricating the mixture of step (i); [C] combining the first component and the second component into a bilayer tablet.
In yet another embodiment, a bilayer tablet may be prepared by:
[A] preparing a first component by the steps of:
(i) mixing atorvastatin with at least one pharmaceutically acceptable
excipient and an alkalizing agent, (ii) granulating the mixture of step (i), (iii) optionally lubricating the mixture of step (ii);
[B] preparing a second component by the steps of:
(i) mixing amiodipine with at least one pharmaceutically acceptable
excipient and an alkalizing agent; (ii) granulating the mixture of step (i), (iii) lubricating the mixture of step (ii);
[C] combining the first component and the second component into a bilayer
tablet.
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The pharmaceutical compositions as described herein may be illustrated by way of the following examples which are not to be construed as limiting the scope of the invention:
EXAMPLE 1

Ingredients Quantity (mg/tablet)
Atorvastatin component
Atorvastatin Calcium 82.87
Lactose monohydrate 251.57
Crospovidone 90.00
Butylated hydroxy anisole 3.60
Butylated hydroxy toluene 0.36
Polyethylene glycol 6.00
Meglumine 24.00
Microcrystalline cellulose 239.60
Sodium bicarbonate 90.00
Magnesium Stearate 12.00
Methylene chloride Q.S,
Purified Water Q.S,
Amlodipine Component
Amlodipine besylate 13.87
Microcrystalline cellulose 369.13
Sodium starch giycolate 8.00
Sodium bicarbonate 5.00
Magnesium stearate 4.00
Coating
Hydroxypropyl methylcellulose 24.00
Titanium dioxide 6.60
Talc 3.00
Polyethylene glycol 2.40
Isopropyl alcohol + Methylene chloride Q.S.
PROCEDURE: Atorvastatin, lactose and crospovidone were mixed and granulated with a solution of butylated hydroxyanisole, butylated hydroxytoluene and polyethylene glycol in methylene chloride and the granules were dried. The granules were coated by spraying an aqueous solution of meglumine over the granules. The granules were dried and mixed with microcrystalline cellulose, sodium bicarbonate and remaining quantity of lactose and crospovidone and the mixture was lubricated by addition of magnesium stearate to obtain atorvastatin component. Amlodipine, microcrystalline cellulose, sodium starch giycolate,
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sodium bicarbonate were mixed and lubricated with magnesium stearate to obtain amlodipine component. The atorvastatin component and the amlodipine component were compressed to form bilayer tablet using appropriate tooling. The bilayer tablets were coated by dispersion of hydroxypropyl methylcellulose, talc, polyethylene glycol and titanium dioxide in a mixture of isopropyl alcohol and methylene chloride,
EXAMPLE 2

Ingredients Quantity (mg/tablet)
Atorvastatin component
Atorvastatin Calcium 82.87
Lactose monohydrate 651.57
Crospovidone 90.00
Butylated hydroxy anisole 3.60
Butylated hydroxy toluene 0.36
Polyethylene glycol 6.00
Meglumine 24.00
Microcrystalline cellulose 239.60
Sodium bicarbonate 90.00
Magnesium Stearate 12.00
Methylene chloride Q.S.
Purified Water Q.S.
Amlodipine Component (Pellets)
Amlodipine besylate 13.87
Microcrystalline cellulose 220.00
Sodium starch glycolate 8.00
Sodium bicarbonate 3.00
Hydroxypropyl methylcellulose 35.13
Coating
Hydroxypropyl methylcellulose 30.00
Titanium dioxide 8.25
Talc 3.75
Polyethylene glycol 3.00
Isopropyl alcohol + Methylene chloride Q.S.
PROCEDURE: Atorvastatin, lactose and crospovidone were mixed and granulated with a solution of butylated hydroxyanisole, butylated hydroxytoluene and polyethylene glycol in methylene chloride and the granules were dried. The granules were coated by spraying an aqueous solution of meglumine over the granules. The granules were dried and mixed with microcrystalline cellulose,
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sodium bicarbonate and remaining quantity of lactose and crospovidone, the mixture was lubricated by addition of magnesium stearate to obtain atorvastatin component. Amlodipine, sodium bicarbonate and hydroxypropyl methylcellulose were dissolved in solvent and the solution was sprayed over microcrystalline cellulose. The drug layered pellets were coated with a solution of hydroxypropyl methylcellulose and sodium starch glycolate to obtain the amlodipine component. The atorvastatin component and the amlodipine component were mixed, lubricated and compressed to form tablets with using appropriate tooling. The tablets were coated by dispersion of hydroxypropyl methylcellulose, talc, polyethylene glycol and titanium dioxide in a mixture of isopropyl alcohol and methylene chloride.
EXAMPLE 3

Ingredients Quantity (mg/tablet)
Atorvastatin component
Atorvastatin Calcium 82.87
Mannitol 255.53
Crospovidone 90.00
Polyethylene glycol 6.00
Meglumine 24.00
Microcrystalline cellulose 239.60
Sodium bicarbonate 90.00
Magnesium Stearate 12.00
Methylene chloride Q.S.
Purified Water Q.S.
Amlodipine Component
Amlodipine besylate 13.87
Microcrystalline cellulose 369.13
Sodium starch glycolate 8.00
Sodium bicarbonate 5.00
Magnesium stearate 4.00
Coating
Hydroxypropyl methylcellulose 24.00
Titanium dioxide 6.60
Talc 3.00
Polyethylene glycol 2.40
Isopropyl alcohol + Methylene chloride Q.S.
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PROCEDURE: Atorvastatin, mannitol and crospovidone were mixed and granulated with solution of polyethylene glycol in methylene chloride and the granules were dried. The granules were coated by spraying an aqueous solution of meglumine over the granules. The granules were dried, mixed with microcrystalline cellulose, sodium bicarbonate and remaining quantity of mannitol and crospovidone, the mixture was lubricated by addition of magnesium stearate to obtain atorvastatin component. Amlodipine, microcrystalline cellulose, sodium starch glycolate, sodium bicarbonate were mixed and lubricated with magnesium stearate to obtain amlodipine component. The atorvastatin component and the amlodipine component were compressed to form bilayer tablet using appropriate tooling. The bilayer tablets were coated by dispersion of hydroxypropyl methylcellulose, talc, polyethylene glycol and titanium dioxide in a mixture of isopropyl alcohol and methylene chloride.
Dated This 30th Day of July, 2008

For Torrent Pharmaceuticals Ltd, Praveen Chand Gandhi
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