FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 1.3)
"ENTERIC COATED PHARMACEUTICAL COMPOSITIONS"
SUN PHARMACEUTICAL INDUSTRIES LTD.
Company incorporated under the laws of India having their office at ACME PLAZA
ANDHERI-KURLA ROAD ANDHERI (E) MUMBAI – 400 059 MAHARASHTRA INDIA
The following specification describes the invention

ENTERIC COATED PHARMACEUTICAL COMPOSITIONS
The present invention relates to pharmaceutical compositions ol' the anti-depressant drug, duloxetine. lor oral administration, a process for preparing .inch formulations and a method of administering to a patient in need thereof.
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). chemically described as (+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propan-l-amine) with the molecular formula ClsHiyNOS. Duloxetine is a white to slightly brownish white solid and is slightly soluble in water. Although the exact mechanism of the antidepressant and central pain inhibitor) action of duloxetine in humans is unknown, the antidepressant and pain inhibitors actions are believed to be because of its potentiation of serotonergic and noradrenergic activity in 1110 central nervous system (CNS). Duloxetine is indicated for the treatment of major depressive disorder and for the treatment of diabetic peripheral neuropathic pain.
Duloxetine is commercially available in United Stales of America as delayed release capsules under the brand name C\ inballa' . I he approved I'yiiibaltu capsulc-> coniani duloxetine hydrochloride equivalent lo 2Umg. 30ing and 6Umg of duloxetine. I lie iuaeti\e ingredients m Unapproved compositions include, hypromellose. hydroxypropyI nietliy Iccliuiose acetate succinate. sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, 1 D&C Blue No.2. iron oxide ycllovs and triethyl citrate.
cymbalta" capsules contain enteric coaled duloxetine pellets comprising a) a core consisting of duloxeiine and a pharmaceutical!) excipient; b) optionally a separating layer ; and c) an enteric-layer comprising hydroxy propy Imethylcellulose acetate succinate and a pharmaceutical!) acceptable excipient.
Duloxeiine hydrochloride is acid labile, and acid hydrolysis of its ether linkage results in a linens I alcohol and I-naplitliol. At pi I 1.0. which is achieved under fasting conditions in \i\o. M)% of drug in the dosage is hydrol)/ed lo 1-naphlhol At a pi I of 2.0. 1 U°\, of the drug in the dosage degrades to I-naplitliol in one hour, and at a pi I ol 4.U. it ad.iiioii would take up u,
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63 hours. This acid sensitive compound has therefore been formulated as enteric coated dosage lorni lo protect ii from degradation.
1 niciic coalings ha\e been used lor man) years lo delay the release of ihc drug from ihe dosage Kirni.v Depending on ihe composition and / or ihickness. the enteric coaliims are resistant lo acidic gastric lluids but are soluble al higher pi I in ihe intestine. Therefore, enteric coated formulations do not release the drug in the acidic gastric lluids where Ihe drug is susceptible to degradation. The enteric coating polymer may be selected from polymers soluble al pi I existing m the upper part of the small intestine or in the latter part of the small intestine and accordingly the release of the drug is delayed by a lime period required for the dosage form to transit lo these pans of the intestine.
However, preparation of stable formulation is problematic if the enteric coating polymer itself leads to inslabililv of the drug. Duloxetine has been found to react with many enteric coalings to form a slowly soluble or an insoluble coating. Further, duloxetine has been found lo react with polymer degradation products or residual free acids present in the enteric polymers. hulow prop\ hnetli) Icellulose acetate succinate (HPMc AS) and h\drox\prop)I methyl cellulose phthalale (III-.VK P) in dosage formulations to form succinamide and phihalainide impurities, ivspeclivelyta.,I'liarm Sci. 199H. Jan; S~( lj:pSl-S5). Ihe rale of formation ol these iinpuriiie.s is further accelerated by heat and humidity.
lo overcome these disadvantages, a number of research endeavors have been directed towards preparing enteric coated pharmaceutical compositions of duloxetine.
Inited Stales Patent No.5, 508.276(the '276 patent) discloses enteric coaled pellets ol'duloxeiine coated with hydroxypropylmethylcellulose acetate succinate as the enteric coaling agent. This paienla covers the C'ymbalta" product and discloses HPMCAS as the compatible enteric coaling agent.
I lined States application No.20060 165776 ( the '776 application) discloses oral pharmaceutical compositions comprising a) a core comprising duloxetine or its pharmaceutical!) acceptable i.lci'ua ati\ es thereof and ihe said core comprises phaniiacculicaiK men nuclei and duloxeinie

mixed and compressed together: b) an intermediate layer comprising one or more polymers c) an enteric polymer comprising one or more enteric polymers; wherein the said composition is tree of alkaline reacting compounds.
It has now been found that, enteric coated pharmaceutical compositions of duloxeline prepared using a neutralized methacrylic acid copolymer as the enteric polymer, are stable.
The present invention can be summarized as below:
A | An enteric coaled pharmaceutical composition comprising :
a) a core comprising duloxeline or its pharmaceulically acceptable salt :
l); a separating laser .surrounding the core:
j) an enteric laser comprising neutralized acrylic acid copoismer surrounding the .separating layerAn enteric coated pharmaceutical composition as in A, wherein the duloxeline of its pharmaceulically acceptable sail is present in an amount ranging from about l%w'w to about 8U%wA\ of the composition.
(.'I An enteric coated pharmaceutical composition as in A, wherein the duloxetine is present as duloxeline hydrochloride.
I)| An enteric coated pharmaceutical composition as in A. wherein the separating layer comprises a pharmaceutically acceptable sugar. \i\ An enteric coaled pharmaceutical composition as in D, wherein the said sugar is sucrose.
I | An enteric coaled pharmaceutical composition as in A. wherein the acrylic acid copolymer is
Mcthacix lie acid-ethyl acrylate copolymer (I.I).
u| An enteric coaled pharmaceutical composition as in i;, wherein the methacrylic acid copolsmcr is present in an amount ranging from about 40%w/\\ lo about 9U%w/w of the enteric laser.
li .An enteric coated pharmaceutical composition as in (J. wherein the melhaerylic acid copolymer is neutralized with a base selected from a group comprising sodium hsdroxide. potassium hydroxide, calcium hsdroxide. magnesium hydroxitie. aluminum hydroxide, ammonia, ammonium hsdroxide. and mixtures thereof
II An enteric coated pharmaceutical composition as in II. wherein the base is used in an amount
ranging from about 0.0l%vs/ss to about 10% vv/w of the enteric polymer.
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The present invention provides, an enteric coated pharmaceutical composition comprising a) a core comprising duloxeline or its pharmaceutical!) acceptable sail: b)a separating layer surrounding the core; c) an enleric laser comprising neulrali/ed acrylic acid copolymer surrounding die separating layer.
The core of the pharmaceutical composition may be a unitary core comprising therapeutically effecli\e amount of duloxeline hydrochloride, or may be multiparticulate.
the term "mulliparticulalc" as ..used herein relcrs to plurality of units, each unit having a size ranging from about 0.1 to about 1.5 mm diameter, and ha\ing a geometrical shape selected from granules, spheroids, beads, seeds and pellets.
The term '"neutralized acrylic acid copolymer" or "neutralized Eudragita L-30 D-55" as used herein, refers to methacrylic acid copolymer which has been totally or partially neutralized by addition of suitable base.
According to the present invention, duloxeline as used herein can also be in the form Us pharmaceutical!} acceptable sail such as acid addition salts like hydrochloride, hydrobronude. sulfate, nitrate, and phosphate; or a salt with an organic acid selected from acelic. propanoic, hvdroxvacetic, lactic, pyruvic, oxalic, malonie, succinic, maleic. I'umaric. maalic, cyclamic. salicsclic. p-aminosalic} lie. and painoic acid. I he hydrochloride salt o! duloxeline is the preferred salt used in the compositions of the present in\ enlioiia. The amount of duloxeline is in the lunge from about I nig lo about lOUutg. more preferably in the range from about lOnig to about 80mg. lypicalK. ihe duloxeline is present in the amount ranging from about l%\\/\\ to about 8()%w/w of the composition. It may be noted that ihe amount of duloxeline or its pharmaceutical!) acceptable salts used in the compositions of the present invention are expressed in terms of %w/w of duloxeline.
According lo one aspect ol' the present invention, the core is prepared by wet granulation technique, comprising the steps ol' blending duloxeline hydrochloride, inannitol. tale and optionally pharmaceutical!}' inert excipients; granulating with a granulating fluid or solution or
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dispersion oi' binder: drying and sizing the granules. These granules can be used for further prucessing like coaling with a separating layer, followed bv coaling will) an enteric layer.
In one embodiment, the core is prepared granulation technique. comprising the step, ol blending duloxetine hydrochloride, lis promello.se, mannilol. tale and optionally pharmaceutical!) inert excipients; dry granulating the blend by roller compactor or slugging; sizing the granules and then layering with a separating layer, followed by an enteric layer.
In another embodiment, the core is prepared by exlrusion-spheronization technique, comprising the steps of blending duloxetine hydrochloride, hypromellose, mannilol, laic: adding water lo the blend and extruding through a extruder; drying the exlrudates and spheronizing the exlrudates in it spheronizer; separating the granules or spheroids to select a desired size and then layering with a separating layer, followed by an enteric layer.
In set another embodiment, the core is prepared by obtaining granules of duloxetine h \ di ochloride and suitable excipients: compressing them to obtain a unit cure: coating the core >\ iih a epaialiiiii las er. lolluwed b\ cuating w ilit an enteric laser.
In a preferred embodiment, the core is prepared by coating inert non-pareil seeds with a laser comprising duloxetine or its pharmaeeutically acceptable salt. Such inert non-pareil seeds arc conventionally used in pharmaceutical science. The most preferred non-pareil seeds are prepared from starch and sucrose which is commonly employed in making pellets for pharmaceuticals. Ikmcser, non-pareil seeds made of any pharmaeeutically acceptable excipient may be used, including, for example microcrystalline cellulose, vegetable gums, waxes and the like.
The non-pareil seeds are coated with a solution or suspension comprsing duloxetine or its pharmaeeutically acceptable salt and a binder, in a suitable solvent or vehicle. examples of binders include, but are not limited to. hydroxyprop) I inethylcelhilose. hydroxy) props Icellulose. puis \ ins Ipvrrolidonc, melh_vlcellulo.se. carboxymethylcelliilose. acacia, gelatin and the like and mixtures thereof. I he preferred binder is hydroxs props lincihs Iccllnlosc I he amount of binder i alines from about 1.0 % lo about 2U%w s\ ol the amount ol duloxetine more preterabls m (lie amount ranging from about 5.0% lo about I0%\s/w of duloxetine.
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According to an embodiment of the present invention, there is a separating layer between the core containing duloxeline. and the enteric layer. The separating layer when used, provides a smooth base for the application of the enteric layer, prolongs the resistance of the core to the acidic conditions, improves stability by minimizing the interaction between drug in the core and the enteric polymer in the enteric layer from coming into direct contact with each other; and also improses stability of drug from light exposure. The smoothing function of the separating layer is purely mechanical, the objective of which is to improve the coverage of the enteric layer and to a\oid ilim spots in it. caused by bumps and irregularities on the core.
I he separating laser of the present invention preferably comprises a sugar. It lias been sound thai, when a pharmaceutically acceptable sugar is added lo the separating laser, the core's resistance to acid conditions is markedly increased. Accordingly, such a sugar mas be included m the separating layer applied to the core as dispersion or solution comprising a polymeric material and other excipienls. A sugar, when included in the separating layer, reduces the quantity of enteric polymer required lo obtain a given level ol acid resistance. The sugar in the separating layer may be present in the amount ranging from about 1.0% to about ]()%w/ss of the total composition.
In addition lo sugar, the separating layer is composed of coherent or polymeric materials and finely powdered solid excipients, which constitute tillers. For example, substances such as hydroxy propyl nielhy Ice II u lose, hydroxy propylcellulose, polyvinylpyrrolidone, nielhy lecllulosc. cark>\y nielhy Icellulose. acacia, gelatin and the like mas be used in small amounts lo increase adheranee and coherence ol the separating laser. The polymeric material in ihe separating laser may be present in the amount ranging from about 0.1 to about I0%\\ s\ of the total composition.
According to an embodiment of the present invention, the enteric laser is present oser the separating layer. The enteric layer contains an enteric material that is stable in acidic medium of the stomach and thereby avoids the direct interaction between the acid medium and the contents ol' the core. Preferably, the enteric coating or layer the present invention comprises a neutralized methacrylic acid copolymer which has been neutralized with a base. More preferably.
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die meihacry lie acid copolymer used in the present invention is the one which is marketed under the trade name I'udragil1' I. 30 D-55.
l-.udragil 1. 30 D-55 is an aqueous acrylic resin dispersion. It is an anionic copolymer deri\ed from meihacry lie acid and ethyl aerya late with a ratio of free carboxylic groups to the ester of approximately 1:1. and has a mean molecular weight of approximately 250.000. Il is supplied as an aqueous dispersion containing 30% SN/VSA of dry lacquer substance, and is marketed by Kolun Pliarma Company, (iermany. 'I'lie enteric polymer is present in an amount ranging from about ■10% to about 90%w/\\ of the enteric layer, preferably between 50% lo about 75% w'w ol'die enteric layer.
According to one embodiment, the preferable base used to neutralize the enteric coating polymer may be selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, ammonia, ammonium hydroxide, and mixtures thereof. Preferably, the base tised for neutralization of inethacrylic acid copolymer is sodium hydroxide. The sodium Iiydroxide may be used in amounts ranging from about 0.01% to about 10% w/w of the enteric polymer, preferably in an amount ranging from about 0.05% to about 5% w.'w olThe enteric polymer.
I he enteric layer of the present invention may include a plaslici/er. surfactant, pigments, anli-adliciviii.s. opacifsnig agents, colorants and the like, which are routinely employed in the preparation ol coating solution or suspension. I he plaslici/ers used in the present nnciilioii may l»e .elected from polyethylene glycol 6000. irielhyl cilrale, iriaeelm, dietiisl phllialale. iribulyl >eb;icaie and the like. 1 he preferred plasticizer in the enteric compositions of the present invention is polyethylene glycol 6000. The anti-adherent is selected from group consisting of talc, magnesium sterate and silicon dioxide. Preferably talc is used as the anti adherent.
.According to an embodiment, the coated multiparticulates of the present invention can be filled into a hard gelatin capsule or optionally mixed with other pharmaceuiically acceptable inert exeipients and compressed into a tablet or minitablets. and these tablets may then be filled into hard gelatin capsules. Alternatively, lhe enteric coated pharmaceutical compositions of the present invention may be provided in lhe form of tablets.
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i'liieric coaled, multiparticulate pharmaceutical compositions of the present iincntion mas be prepared according to the following process:
a) A dispersion of dtiloxetine hydrochloride is prepared by homogenizing duloxeline hydrochloride, hypromellose. mannitol and talc in water.
b) The homogenized drug dispersion is sprayed on to the sugar spheres in a fluidized bed processor.
e) The pellets are dried till moisture content is less than l%w/w.
d) The intermediate coating solution is prepared by dispersing talc in aqueous solution of hypromellose and sucrose.
e) The solution obtained in step d. is sprayed over the drug pellets obtained in step c.
I) The enteric coaling solution is prepared by adding a dilute solution of sodium hydroxide lo the aqueous dispersion ol methacrslic acid copoh'iner followed bs addition ol aqueous solution of pols ethylene ghcol. titanium dioxide, plossorbate XU and talc dispersion, wherein the pi I of the enteric coaling solution is kepi at pi I 5.0.
g) The enteric coating is applied over pellets obtained in slep e.
h) The enteric coated pellets obtained are then filled into hard gelatin capsules.
It will be understood by those of skill in the art that numerous modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood thai the following examples are illustrative only and should not to be construed lo limit the scope ol' the present invention.
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COMPARATIVE EXAMPLE 1
l-nteric coated pharmaceutical compositions of Diiloxetine hydrochloride were prepared as shown in table I below.
Table 1

S.No Ingredients Quantity (nig/cap)
Core pellets
1 Sugar spheres 124.81
i Diiloxetine 1Is drochlonde 07 30
3 1 Is promeilose 2910 00.73
4 Manniiol 13.46
5 Talc J. 3 7
Separating layer
1 llypromellose 2910 19.17
i Sucrose 14.38
laic 9.57
Enteric layer
1 Pudragit L 30D 55 (on dry solid content basis) 80.00
i Polyethylene glycol 6000 7.81
i j Talc 24.64
4 Titanium dioxide 0.87
5 Polysorbate 80 3.55
Process ol manufacture:
A homogenized dispersion oi' Diiloxetine hydrochloride was prepared in aqueous solution o\' In pi\iiucllose and llien niannitol. laic were added lo the dispersion. I he homogenized drug dispersion was llien sprayed on lo the sugar spheres in a lluidiz.cd bed equipment. I he drug pellets were then dried lill the moisture content was less than l.0%w/w. I he intermediate laser coating solution was prepared by dispersing talc in an aqueous solution of hypromeilose and sucrose. This solution was applied over drug pellets in a fluid bed equipment (1 Bf) lo form the separating laser. A coating solution was prepared by mixing aqueous solution of polyethslene glvcol in methacrylic dispersion and then adding talc dispersion lo the same. An enteric laser was applied over these coated pellets. The enteric coated pellets were dried in l-'BP lill moisture was not more than 1.0%w/w. The enteric coated pellets were then filled in hard gelatin capsules.
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An invilro dissolution test was conducted for these duloxetine hydrochloride delayed release capsule compositions of comparative example I. The testing was performed using USP I s pe I dissolution apparatus, operating al 37"C with a basket rotating at a speed of 50 rpm. The capsule: were tested in 900ml. 0.1N hydrochloride for first 120 minutes, followed b\ 900ml of pi I 6.8 phosphate buffer lor 90 minutes. The results are shown in table 2 below:
Table 2: Dissolution profile of Duloxetine hydrochloride delayed release capsules ol' eoiiiparative example 1

Time (minute) Cumulative percentage (%) of duloxetine hydrochloride

120 3.46

15 03.51
30 18.3.8
45 32.74
60 47.72
90 61.96
flic analysis of duloxetine hydrochloride from the capsules was measured using 11 PLC and the
results arc shown in table 3 below:
Table 3

Type of Impurity Percent (%)
Single Maximum impurity 0.14
Total Impurity 0.26
It is e\ idem from fable 2 above that a maximum release ofonly about 60% of duloxetine was possible. Also, table 3 indicates that a total impurity of 0.26% was formed.
1 1

The compositions prepared as per comparative example I, were charged al 60 T' lor 3 days. The results of dissolution study at the end of 3 days is summarized in table 4. while Hl-M.C analysis results are summarized in 'fable 5 below.
Table 4

Time (minutes) Cumulative percentage (%) ofduloxetine hydrochloride
Comparative Example 1

120 8.46

15 2.42
30 7.76
45 21.55
60 33.50
90 51.34
Table 5

Type of Impurity Percent (%)
Single Maximum impurity 0.66
Total Impurity 1.16
may be noted from fables 4 and 5 above that at the end of 3 days at 60"C the capsules were found to release only about 50% ofduloxetine, and the total impurity had gone up to 1.16%.
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Example 1
linteric coaled pharmaeeulieal compositions of the present invention comprising duloxetine hydrochloride are summarized in table 6 below.
Table 6

S.N0 Ingredients Quantity(mg/cap)
Core pellets
1 Sugar spheres 124.81
2 Duloxetine Hydrochloride 67.30
Hypromellose 2910 06.73
4 Mannitol 13.46
5 laic 3.37
Separating layer
1 Hypromellose 2910 19.17
"> Sucrose 14.38
-> laic 9.57
Enteric layer
1 luidragit L 30D 55 (on dry solid content basis) 80.00
i Polyethylene glycol 6000 7.81
3 Talc 24.64
4 Titanium dioxide 0.87
5 Polysorbate 80 3.55
6 Sodium Hydroxide 0.51
Process of manufacture:
A homogenized dispersion of Duloxetine hydrochloride was prepared in aqueous solution of hypromellose and then mannitol and talc were added to the dispersion. The homogenized drug dispersion was then sprayed on to the sugar spheres in a lluidiz.ed bed equipment. The drug pellets were dried lill the moisture content was less than ].0%w/w. A coating solution was prepared by dispersing talc in an aqueous solution of hypromellose and sucrose. The solution was applied over drug pellets in the fluid bed equipment (IBI7) to form the separating layer. A second coaling solution was prepared by adding a dilute solution of sodium hydroxide to an aqueous dispersion of methacry lie acid copolymer followed by addition of aqueous solution o\' pul_\ethylene glycol and talc dispersion. I he pi 1 of the enteric coaling solution thus obtained was maintained at pi I 5.0. This was then used to form ihe enteric layer. I lie enierie coaled pellcis were dried in ITili lill moisture content was not more than 1.0%w,w. I he enteric coaled pellets were then III led in hard gelatin capsules.
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Example 2
The im iiro dissolution tests were conducted for duloxetine hulrocliloride delayed release capsule compositions of example I. I'he testing was performed using USF I ypc I dissolution apparatus, operating at 37V with the basket rotating at a speed of 50 rpm. The capsules were tested in 900ml, 0.1N hydrochloride for first 120 minutes, followed by 900ml of pi I 6.8 phosphate buffer for 90 minutes. The results are shown in table 7 below:
Table 7: Dissolution profile of Duloxetine hydrochloride delayed release capsules
of example 1
Time (minute) Cumulative percentage (%) of duloxetine hydrochloride

120 2.05

15 34.08
30 86.15
45 93.04
_.<>° . . _, 96.28
90 97.4 5

1 IP1.C analysis of

duloxetine hydrochloride shown in table 8 below:
Table 8

Type of Impurity Percent (%)
Single Maximum impurity 0.03
Total Impurity 0.06
The dissolution showed a complete release of drug when pellets were coated with neutralized mcthacrylic acid copolymer, suggesting that neutralization oi' free carboxylic acid groups present in the polymer is necessary to restrict the interaction between free acid groups and drug. Degradation was also found to be significant!) less in comparison to composilioiis ol' cumparat example I.
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Example 3
I he compositions of the present invention prepared as per example 1. which were charged ai oOV for i da\s. I'he invitro dissolution tests were conducted for duloxeiine hydrochloride dekncd release capsule compositions of example I. I he testing was periormed using L SI' Tspe
I dissolution apparatus, operating at 37 'C with the basket rotating ai a .->peed of 50 rpm. I lie capsules were tested in 900ml, 0.1N hydrochloride for first 120 minutes, lollovved by 900ml oi' pi I 6.8 phosphate buffer for 90 minutes. Hie results of dissolution study obtained are summarized in table 9 below, and HPLC analysis result is summarized in table 10 below.
Table 9

Time (minutes) Cumulative percentage (%) ofcluloxetine hydrochloride
Example 1
120 6.23

15 40.41
30 93.25
45 97.26
60 97.87
90 98.9-1
PLC analysis of duloxeiine hydrochloride shown in table lu below:
Table 10

Type of Impurity Percent (%)
Single Maximum impurity 0.04
Total Impurity 0.1 1
Dated this 18"'day of May, 2007.

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