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(ll) PateotNum.ber: KE 377

(4S)Dateor..-ont' 18/03/2010

(51) Int.Cl.7 A 61K 31/137, 9/32, 9136, 9/48

(21) Application Number: KE/P/2004/ 000384

(22) Filing Date: 27/10/2004

(30) Priority data: 117!MUM/2004  04/02/2004  IN and 980!MUM/2004 13/09/2004 IN

(73) Owner:ALEMBIC LIMITED of  ALEMBIC ROAD ,V ADODARA 390 003, GUJARAT, India

(72) Inventor:

KSHIRSAGAR, Rajesh; BHATTACHARYA, SAMPAD; KSHIRSAGAR, RAJESH; JOSHI, MAYANK, PAND!TA, SANDIEEP; JOSHI, Mayank andPANDITA, Sandeep

(74) Agent/address for correspondence:

Kaplan & Stratton Advocates, P.O. Box 40111-00100, Nairobi
 
(54) Title:EXTENDED RELEASE COATED MICROTABLETS OF VENLAFAXINE HYDROCHRORIDE

(57) Abstract:The present invention relates to an extended release once daily pharmaceuatical formulation comprising venlafaxine hydrochloride and pharmaceutically acceptable excipients.

More particularly , the present invention relates to extended release composition in the form of the mini-tablets which are incorporatedin hard gelatin capsules.

conveutional immediate release tablets or as 24 hours extended-release multiparticulate capsules. Venlafaxine hydrochloride is approved for sale in various coun1rles including the United States of America under the hrand name EFFEXOR.R'IM. (Wyeth Ayerst). It is available as an immediate release tablet and as an extended release capsule under the
5    hrand name EFFEXOR.RTM. (Wyeth Ayers!) and EFFEXOR XR.RTM. (Wyeth Ayerst), respectively.

Veulafoxine hydrochloride is very soluble in water. It is known that it is very difficult to develop a pluumac\lllfical form with a very slow dissolution rate of freely soluble drug.
lO

U.S. Pat. No. 6274171 and related EP 0797991 disclose ~sulated extended release formulations form venlafaxine hydrochloride. A once daily, encapsulated extended release dosage form is disclosed that provides a flatiened drug plasma profile and reduces the adverse side effects. The OIWapsulated dosage form is taught to comprise spheroids of

15 venlafaxine hydrochloride, microcrystalline cellulose, and hydroxypropylmethylcellulose (HPMC). These spheroids are coated with a mixture of ethyl cellulose and HPMC. By providing an appropriate amount of the coating, the desired blood plasma profile can be
obtained.

20    U.S. Pat. No. 6274171 and EP 0797991 also state that forming an extended release dosage from of venlafaxine hydrochloride was difficult in part due to the high water solubility of the hydrochloride salt. In fact, these patents disclose that "[n]umerous attempts to produce extended release tablets by hydrogel teclniology proved to be fruitless

because the compressed tablets were either physically unstable (poor compressibility or

25    : copping problems) or dissolved too rapidly in dissolution studies." Unlike the encspsulated extended release formulations described in these patents, a hydrogel extended release venlafaxine hydrochloride tablet is taught to typically exhibit a dissolution profile wberein 40"/o-50"/o is released within 2 hours, 60"/o-70% is released within 4 hours, and 85%-100% is released within 8 hours.


W099122724 also discloses encapsulated venlafaxine hydrocbloride extended release dosage fumls. These fonnulations differ from those in U.S. Pat. No. 6274171 and EP 0797991 in that the spheroid is substantially free ofHPMC.

5    AltholJI!h a venl~ extended release capsule has been produced, it would be advantageous to provide a leas complicated dosage fonn thst nonetheleas provides extended release ofvenlafaxine.

W094127589 and WOOI/37815 describe osmotic dosage fumls Containing venlafaxine

10    hydrochloride.

US 20030190354 discloses an extended release composition comprising as active compound venlafaxine hydrocbloride in a matrix tablet dosage form, in which venlafaxine hydrocbloride is mixed with a combination of hydrophilic and hydrophobic

15    matrix funning ccmponents. The matrix components are suitably combination of high and low viscosity grades hydroxyl propyl methyl cellulose, ethyl cellulose, glyeeryl behenate and methyl cellulose. Two granulation methcds were used for. the production of the tsblets: the first was a regular one step grll!lulation process, in which all excipients were

blended together with the active, then wet granulated with Kollidon SR, dried, milled and

20    compressed into oval shape scored ~lets. The second granulation process was a two step process, the first was wet granulation of the active material, which was blended with the
hydrophobic compcnents salected from Ethocel or   Compritol.  Later on, the milled

•    gtanulate was mixed Wiil:i-thehydropJiilic compcnents, the methoceJS Widtlieliibilcating compcnents, syloid 244 and Mg stearate.

25

W003/55475 teaches the controlled relealje fonnulation of venlafaxine. The phannaceutical formulation of the present invention comprises for example a core ccnsistiog of an active drug which may be advantageously in amotphous fonn, pclyvinylpyrrolidone, a combination of two hydrophilic pclymers having different


for film coating may be optionally added thereto. The combination of the cBI,rlers i.e. the water soluble polymer, polyvinylpyrrolidone and the low viscosity hydrophilic polymer has a dcuble effect and the advantage that it stabilizes the amorphous fonn of the active ingredient and simultaneously modifies the release of the amorphous active ingredient in

5    such a way that it is sustained, repeatable and independent of the omo1phous or polymo1phous form of the active ingredient, its particle size and specific sur:fiwe area.

WO 03/53402 and related US 2004133982 discloses• zero-order sustained release dcsage

forms.  A  solid  dcsage  form  comprising  a  matrix  core  comprising  intragranular

10    ethylcellul...;, and a Wll!er soluble active agent granulated and compressed together with extragranular ethyl cellulose and a film coating comprising a hydrophobic polymer

wherein the film coating completely encases the matrix core. This_lnv.mtion also relates

to a process for manufacturing a zero-order sustained release tablet containing a water-

soluble active agent, comprising the steps of :(a) preparing a  first admixture comprising

15    the active agent and intragranular ethylcellulose;(b) granulating the first admixture in order to obtain a granular prod~t;(c) preparing a second admixture comprising extragranular ethylcellulose;(d) preparing a third admixture comprising the pular product and the second admixture;

20    W004/12699 and related US 20040096501 tesch the use of dusl retard technique to effectively control the release ride of modified release active ingredient by using small quantity of release controlling agents. This dusl retard technique thus sufficiently reduces the-size• of the dcsagcd'onn, -which is convenient •fol' swallowing. The dosage fonn

comprises of a) Micro matrix particles containing high solubility active ingredient and

25    one or more hydrophobic release controlling agent, b) Coating of Micro matrix particles with one or more hydrophobic release controlling agents.

Extended release preparation of drugs are advantageous in the administration because of

their reduced dcsage frequency. The frequency can be reduced by maintaining coustant

30    plasma concentration of drug over an extended period of time to ensure extended effect of active ingredient.
OBJECTIVES OF THE INVENTION

It is an object of the present invention to provide an extended release of the active ingredient from the pharmaceutical composition, which bas blood plasma levels above minimwn therapeutic Concentration over extended period of time.

5

Another object of the present invention .is to provide extended release pharmaceutical composition for once daily dQsage form.

Yet  another  object  of  the  present  invention  is  to  provide  an extended  release

10    pbarmaceuticai composition, which releases the 8ctive ingredient in predetermined manner.

Yet another object of the present invention is to produce the formulation by a conventio!lal method so as to reduce the process time.

Yet another object of the present invention is to develop extended release formulstion of

venlafaxine hydrochloride which is bioequivalent to Effexor XR by conventional method comprismg compression and coating.

20    SUMMARY OF THE INVENTION:

Accordingly,  the present  invention  relates  to  an  extended  release  pharmaceutical

formulation compriaing venlafaxine hydrochloride, diluent, water-solubl~ component and

W!iiOI• iliSoluble P.,Jyn'ler llliilo!her ~tical acceptable excipients.

25    The components are selected in such a way to give extended release of the venlafaxine hydrochloride in a predetermined manner.

The invention relates to extended release composition in the form of mini-tablets which

are incorporated in hard gelatin capsules containing a therapeutically effective amount of

30    the mini-tablets comprised of venlafaxine hydrochloride, microcrystalline cellulose, polyvinyl pym>lidone and optionally conventional excipients and further coating of mini-tablets comprising of ethyl cellulose and plasdone S630 copolyvidoniwn (ISP
 
technologies). The tablets of the invention exhibit specific dissolution profiles, especially with venlafaxine HCI.

Preferably,  the  present invention relates  to  the extended release  formulation  wbicb

5    comprises from about 40"A> to about 80% by weight of a venlafaxine hydrochloride; from about 25% to about 45% of microcrystalline cellulose and from about 0.5% to about 10% polyvinyl pyrrolidone of the total weight of composition. The coating on mini-tablet comprises of from about 2% to 15% of total weight of the composition. The coating

composition comprises  from about 50% to about 95% ethylcellulose and from about 3%

10    to about 50"A> ofplasdone S-630 copolyvidonium (ISP technologies) of the total weight of the coating layer.

More preferably the present invention relates to the extended release formulation which

comprises from about 48% to about 68% by weight of a venlafaxine hydrochloride; from

15    about 26% to about 38% of microcrystalline cellulose and from about 2% to about 9% of polyvinyl PYrrolidone of the total weight of composition. 'g..coating on mini-tablet comprises of from about 4% to 14% of total weight of the composition. The coating on

mini-tablet eomprises of from about 65% to about 95% ethylcellulose and from about 5% to about 40"A> of plasdone S-630 copolyvidonium of the total weight of the coating layer.
20

Still more preferably the present invention relates to the extended release fonnulation wbich comprises from about 57% to about 62% by weight of a venlafaxine hydrochloride; from about 27% to about 32% of microcrystalline cellUlose and from about 2.5% to about 5.5% of polyvinyl pyrrolidone of the total weight of composition.

25    The coating on mini-tablet comprises of from about 6% to 12% of total weight of the composition. The coating on mini-tablet comprises of from about 70"A> to about 80% ethylcellulose and from about 20% to about 30% of plasdone S-630 copolyvidonium of the total weight of the coating layer.

30    According to the present invention, the extended release formulation is prepared by compression followed by functional coating method, the said method comprising steps of:


i.    Blending the venlafaxine hydrochloride and diluent.

ii.    Oranulating the blended mixture with an aqueous or non-aqueous solution of

binder and drying it.

iii.    Lubricating  the  dried  granules  and  compressing  into  tablets  of appropriate

5    shape (3 - 6 mm in diameter).

iv.    Coating the tablets with an aqueous or non-aqueous dispersion of water insoluble and water soluble polymer.
v.    Filling coated mini tablets obtained in step (iv) into capsule of appropriate size.

10    Such 12, 6, 3 mini-tablets are filled into pharmaceutically acceptable capsule to form 150 mg. 75 mg and 37.5mg strengths respectively ofvenlafaxine.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, the hard gelatin capaule comprises of film

15    coated mini-tablets. These mini-tablets comprised of active ingredient, binder and water-soluble component and optionally conventional excipients. These mini-tablets are coated with combinstio~ of water-soluble and waters insoluble polymer.

According to the present invention, the pharmaceutical composition contains venlafaxine

20    hydrochloride as an active ingredient. The venlafaxine hydrochloride may be present in an amount from about 40 % to abOut 80%, preferably from about 48% to about 68% by
weight, more preferably from about 57% to about 62% of the total weight of extended •rerea.e oompost'tion.-

25    Further, ven1afaxine hydrochloride may be present in an amount from 12.5mg to 400mg per capsule.

According  to  the  embodiment  of the  present  invention,  the  mini-tablet  contains

microcrystalline cellulose as diluent. Microcrystalline cellulose may be present in an

30    amount from about 25 % to about 45%, preferably from about 26% to about 38% by weight, more preferably from about 27% to about 32% of the total weight of extended release composition.

Aocording to the embodiment of the present invention, the mini-tablet contains polyvinyl

pyrrolidone as binder. Polyvinyl pyrrolidone may be present in an amount from about 0.5

% to about 10"/o, preferably from about 2% to about 9% by weight, more preferably from

5    about 2.5% to about 5.5% of the total weil!bt of extended release composition.

In addition to the above ingredients, pbarmaceutical grade magnesium stearate/stearic acid as a glidalrt, talc as an anti•adb~ and colloidal Silicion dioxide as a lubricant are

included in the mini-tablet. Preferably, magnesium stearate/stearic acid, talc and colloidal

10    silicion dioxide are present in amounts in the range of 1% to 6% by weight either alone or in combination.

In an embodiment of the present invention, the coating on mini-tablet comprises of water

insoluble polymer and wuter-scluble polymer.  The water insoluble polymer is selected

15    from the group consisting of cellulose ether such as othylcellulose, a cellulose ester such as cellulose acetate, methacrylic derivatives available from Rohm Pharma under the trade name "EudragitRlM."RL, RS and NE, etc. In a preferred embodiment, the water insoluble polymer is ethyl cellulose present in an amount from about 50"/o to about 95% by weight of the functional coating content of extended release composition.
20

In an embodiment of the present invention, 1he coating on mini-tablet alsc contains water-

soluble polymer. The water soluble polymer is selected from the group consisting of

Plasdone S-'630 copolyvidonwn  (ISP technologies), hydrated colloidal silica, sucrose,

mannitol  or  any  other  substance  capable  of  playing  the  same  role.  In preferred

25    embodiment, the water soluble polymer is Plasdone S-630 copolyvidonum (ISP technologies) which is present in an amount from about 3% to about SO% by weight of the functional coating content of extended release composition.

Ethyl cellulose, an ethyl ether of cellulose, is a long-chain polymer of

30    b-anhydroglucose units joined together by acotallinkages. It is tasteless, free flowing. white to light tan colored powder. It is a stable, sligbtly hygroscopic material. It is prsctically insoluble in glycerin, propylene glycol and water. Ethylcellulose that contains

less than 46.5% of ethoxyl groups is freely soluble in chloroform, methyl acetate and totrahydrofuran and in mixtuies of aromatic hydroclllbons with ethanol (95%). Ethylcellulose that contains not less than 46.5% of ethoxy groups is freely soluble u; chloroform, ethanol (95%), ethyl acetate, methanol and toluene. It is chemically resistant

5    to alkalis, both dilute and concentrated and to salt solutions, although it is more sensitive to acidic materials than are cellulose esters. Ethyl cellulose polymers exhibit good stebility within the pH range of3 to II, so they con be used with both acidic and alkaline ingredients.

10    The viscosity of ethyl cellulose is meosured typically at 25°C using 5%wlv ethylcellulose dissolved in a solvent bleud of 80"A. toluene: 20% ethanol (w/w). Different grades of elhYlcellulose are ethOcel std 4 premium, ethocel std 7FP premium, ethocel std 7 premium, ethocel std IOFP premium, ethocel std lOP premium; ethocel std 20P premium,
ethocel std 45P premium, ethocel std I OOFP premiUm, ethocel  I OOP hsving viscosity

15    range of3-5.5 cP, 6-ScP, 6-ScP, 9-11 cP, 9-llcP, 18-22cP, 41-49cP, 90-l!OcP, 90-l!OcP respectively. The viscosity of on ethylcellulose solution increases with on .increase in ethylcellulose concentration. The viscosity of such solutiolis depends almost entirely on

the alcohol content and is independent of toluene. In addition, nonpharmaceuticBJ grades of ethylcellulose that differ in their ethoxyl content and degree of polymerization are

20    available. Ethyl cellulose is prepared by treating purified cellulose with on alkaline solution, followed by ethylation of the alkali cellulose with chloroethone.

Plasdone S-630 copolyvidonum (ISP technologies) is a synthetic water-soluble copolymer c6DSiStirig ofN-ViiiYI-2'pytJirolidine and Vinyl acetate in a random• 60:40 ratio. Plasdone S-630 copolyvidonum has low hygroscopicity. AJ 50"A. RH level, Plasdone S-

25    630 copolyvidonum gains less than I 0% weight and does easily desorb the gained moisture. It is on excipient of choice for moisture sensitive drugs.

The K-value for Plasdone S-630 copolyvidonum is specified between 25.4 and 34.2. The

K-value is calculated from the kinematic viscosity of a I% aqueous solution and hence is

30    related to the average molecular weight of the polymer.

Plasdone S-630 copolyvidonmn is a highly effi>ctive film forming adhesive. It is used primarily as a tablet binder, although its UDique properties Jlllllre it useful in the fotmulation and coating ofa variety of pharmaceutical dosage fotms.

5    Plasdone S-630 copolyvidonwn is aoluble in many solvents and can be used in non-aqueous grauulation or coatings. It is suppiied as a free-flowing spray-<lried powder to ensme maximmn handlirig efficiency. Spray drying results in spherical particles with tightly controlled particle size distribution. The particle morphology is responsible for the
excellent powder flow properties, which aids blending with other excipients.

10

According to a proooss for making tho cOmposition of tho present invention, tho venlafaxine hydrochloride is blended with microcrystalline cellulose and granulated using binder aolution. These grauules are then compreaaed into DUni-tablets. The resulting mini-tilbl~ are then coated with extended release polymer.

~5

In an embodi!neol of tho present invention, tho functional coating is done by dissolving etbylcellulose and plasdorie S 630 copolyvidonmn in a aolvent such as ethyl alcohol The resulting si>lution is sprayed onto tho mini-tablet cores, using a coating pan or a perforated twbine or a fluidized bed apparatus.

20

In an embodi!neol of tho present invention, tho woiglit ratio of functional coating/tsblot is

""''lprised  e.g.  between  0,02  and 0.15,  preferably  between  0.04  and 0.14,   more

--~0.060rid0.12:-

25    The mini-tilblot size ranges between 3 - 6 mm in diameter.

Preferably, venlafaxine hydrochloride and diluent are sifted through suitable mesh sieve and• tho sifted •mass is blended using high shear mixture and the blended mass is

granulated with aqueous or non-aqueous binder solution and tho granulated mass is dried

30    until tho moisture content is less than 4% w/w and tho dried mass is passed through suitable mesh sieve aDd this grauulos are lubricated with lubricants, glidants, ~adherants. The lubricated granules are compresaed into mini-tablets o{ appropriate

size (3 - 6mm in diameter). The mini-tablets are further coated with coating of W!ller soluble and water insoluble polymer. These film-coated mini-tablets are filled into hard gelatin capsule.

5    The preseot invention is illustrated by the fOllowing examples.

EXAMPLES

General procedlU'e for tho preparation of extended release cansule contnining minl-

table!B

10

VenlaJiixine hydrochloride and microcrystallino cellulose is sifted through suitable mesh sieve and the sifted mass is blended using high shear IDixture and the blended mass is granulsted with aqueous polyvinyl pyiiO!idone solution Orul the granulated mass is dried until !lui moisture content couies down to less th8n 4% w/w and the dried mass is passed
15    through suitable mesh sieve and this granules are lubricated with magnesium stearate, colloliu silicon dioxide and tslc and the lubricated granules are compressed into mini-tablets.

These mini-tablets  are coated with aqueous or non-aqueous dispersion of functional

20    coating of W!ller soluble and water insoluble polymer. The diameter of film-coated mini-tablet ranges between 3 - 6 mm. •These mini-tablets are then filled into hard gelatin capsule.

Such 12, 6, 3 mini-tablets are filled into pharmaceutically acceptable capsule to fonn !50

25    mg, 75 mg and 37 .Smg strengths respectively ofvenlafaxine hydrochloride.

Dissolution Method

For all examples, the capsule containing tablets were tested for dissolution ofvenlafaxine

hydrochloride in  900ml of W!ller as dissolution media at 37°C and in 40-mesh basket

30    (USP Type 1) and roteted at IOOrpm.

In the following examples, the composition and its dissolution profiles are given in a

tabular form.

EXAMPLE I

5

Composition

        rn-dient    Weight (mg/tablet
        Venlafaxine HCI    14.27
        Cellulose    7.13
        Povidone    1.10
        Ethyl Alcohol    q.s
        Talc    0.25
        Colloidal Silicon Dioxide    0.25
        Magnesium Stearate        0.50
        Ethyl Cellulose    1.22
        Com>lYVidone    0.37
        Ethyl Alcohol    q.s.
        Totnl Weight    25.09
10    Dissolution Profile   
           
        Time (hour)    Percent   venlafaxine
                HCl released
        I    0
        2        13
    •o~    38
        8        62
        12        75
        24        92
15               
           
EXAMPLEl                   
Composition                   
                           
    I lru!redient                Weillht  mllltablet
    Veolafilxine HCl                14.27   
    ine cellulose        7.13   
    Povidone            1.10   
    Pure Water        I q.s.
    Talc        0.25   
    Colloidal Silicon Dioxide    0.25   
    Magnesiwn Stearate    0.50   
    Ethvl Cellulose        !.59   
    Cormlvvidone                0.48   
    Ethyl Alcohol        I q.s.
    Total Weil!ht        25.57   
5Dissolution Profile                   
                       
    'T"!me(hour)        Peroent   venlafilxine   
                HCl released   
    I        0.2   
    2            7.7   
    4            23.2   
    8            46.2   
    12            60           
    24            81.9   
EXAMPLE3                   
Composition                   
                       
    Ingredient                Weight (riiJtTtablet)
                           
    Veolafilxine HCl            14.27   
    Mi        cellulose        7.13   
    Povidone            1.10   
    Pure Water            I Q.S.
    Tale            0.25   
    Colloidal Silicon Dioxide        0.25   
    Magnesium Stearate        0.50   
    Ethyl Cellulose            1.08   
    I Copolyvidone            0.32   
    Ethyl Alcohol            I q.s.
    TotalWell!:ht            24.9       
Dissolution Prorde           
                   
        Time (hour)            Percent   Venlafaxine
                    HCI released
        1            6.2
        2        22.7
        4        48.8
    8        77.5
    12            92.2
        24            102.7


5    EXAMPLE4

Composition

        lnmdient            Weiglrt (IDg!tablet)   
        Venlafaxioe HCI        14.27       
        Mi    e cellulose        7.13       
        Povidone            1.10       
        Pure Water            Q.S.   
        Talc            0.25       
        Colloidal Silicon Dioxide        0.25       
        MaRnesium Stearate        0.50       
        'Eudragit RS 300        3.15       
        Talc            0.16       
        l:friethv1 Citrate            0.19       
        Pure Water                q.s.   
                           
        Total Weildlt            27.00       
Dissolution Profile                   
10                               
                       
        Time (hour)        Percent   Venlafaxine       
                    HCI released       
    1            8           
    2            9           
        4            12           
        8            85           
        12            104       
        24            -           


Further, when the composition of the present iD.vention was extruded, spheronized and dried to form spheroids instead of mini-tablets as envisaged in the present invention, the dissolution profile was more immediate, which is unsuitable for once daily adnrlnistration, as shown in the accompanying example:

5

ExampleS

Composidon:

    Sr.    I Jruzredient .    Qty/Capsule (150 I!Dl)   
    No.           
            CORE       
    I        Venlafaxine HCI    171.24   
                   
    2        Microcrystslline Cellulose    85.56   
                   
    3        .Povidone    13.20   
                   
    4        Water    Q.S.   
            COAT    270.00   
    8        Ethyl Cellulose    19.500   
    9        Copolyvidone    5.86   
                   
    10        Ethyl Alcohol    q.s.   
                   
                   
            TOTAL WEIGHT    295.36   
10

A uniformly blended mixture of Venlafaxine Hydrochloride (171.24 g)• and microcrystalline cellulose (85.56 g) was granulated into an over wetted dough using solution of povidone (13.2 g) in water. The plastic mass was extruded, spheronized and dried to prepste uncoated spheroids. The cylindrical extrudes of the composition were

15    very sticky and fragile with varishle length of the extruded cylinders which resulted into

non-uniform spheroids daring spheronizstion. The extrudes were diffiCI!it to spheronize. The formed spheruids were irregular shsped and excessively sticky in nature which


resulted in the. formation ohggregates. Aggregates were remowd by sieving after drying the SJ?heroids. The I!Pheroids were further coated in a wurster type fluid bed cooter with a solution of 19.5 g of Ethyl cellulose and 5.86 g of Copolyvidone in Ethyl alcohol. The fragile nature of the I!Pheroids resulted in formation of too many fines while coating. The

5    presence of fine bridged the formation offew aggregates during coating. The film coated spheroids were siewd to remove those aggregates and then filled into pharmaceutically acceptable capsules.

The in vitro drug dissolution studies were condncted on the formed I!Pheroids using USP I

10    at 37"C and 100 1'J]lll in 900 mi water. The drwz release was as follows:


Time    Pereent Venlafaxlne
I (Hours)    HCI released
I    21
2    84
4    99

The dissolution profile suggests that preparing spheroids of the composition claimed in

15    the present inwution would have a more lmmediate drug release characteristics unsuitable for once daily administration. The said invention is thus only worl<able for mini-tablets of diameter greater than 3 mm and not for I!Pheroids of diameter less than 2 mm.

20    Blopbarmaeeutig:

A randomized, two trealment, two period, two sequence, siogle dose, crossover bioavsilability study on Venlafaxine ISO mg extended release capsule (Example I),

compared with Venlafaxine hydrocbloride  ISOmg  extended release capsule  (Effexor

XR"") manufllctured by Wyeth Ayers! laboratories, USA, in 12 healthy, adult, male,

25    human subjects was conducted under fasting conditions. The mean drug plasma level are shown in Figure I and the phannacokinetic parameters are recorded in Table I.

        Parent    Metabolite   
                       
Parameter    Unit    Eump1el    Eft'exorXR    Example I    Eft'exorXR   
                       
Cmax    nglmL    101.28    106.183    162.33    166.025   
                       
Tmax    h    7.67    8.500    11.25    12.17   
                       
AUC(O->t)    ng.b/mL    156o.62    1669.10    4119.86    3949.95   
                       
AUC(O->Inf)    ng.hlmL    1635.48    1823.616    4740.36    4494.14   
                       

1.    An extended relea..e formulation of venlafaxine hydrochloride in the form of mini tablets filled in hard gelatin capsule, said mini tablets having a core and an outer
•5 coating ,the core of the said mini-tablets comprising venlafaxine hydrochloride, microcrystalline cellulose and polyvinylpyrrolidone and the said coating comprising a water insoluble polymer and ~water soluble polymer.

2.  An extended release formulation of venlafaxine hydrochloride according to claim 1,

10    comprising of 40 - 80"/o of venlafaxine hydrochloride by weight of each of the mini-tablets, 25 - 45% of microcrystalline cellulose by weight of each of the mini-tablets,

0.5 - 10% of polyvinylpYrrolidone by weight of each of the mini-tablets, the said mini-tablets being coated with a coat comprising 2 - 15% of the total weight of the mini-tablets, wherein the coating comprises of SO - 95% of a water insoluble

15    polymer and 3 - SO% of a water soluble polymer.

3.    An extended release formulation of venlafaxine hydrochloride according to claim 2, comprising of from about 48 - 68% of venlafaxine hydrochloride by weight of each of the mini-tablets, from about 26- 38% of microcrystalline cellulose by weight of

20    each of the mini-tablets and from about 2 - 9% of polyvinyl pyrrolidone by weight of each of the mini-tablets; the said mini-tablets being eoated with a coat comprising 5 - 14% of the total weight of the mini-tablets, wherein the coating comprises of 65 - 95% of a water insoluble polymer and S - 40% of a water soluble polymer.

4.  An extended release formulation of venlafaxine hydrochloride according to claim 3,

25    comprising of from about 57 -  62% of venlafaxine hydrochloride by weight of each

of the mini-tablets, from about 27- 32% of microcrystalline cellulose by weight of each of the mini-tablets and from about 2.5 - 5.5% of polyvinyl pyrroli~ne by

weight of each of the mini-tablets; the said mini-tablets being coated with a coat comprising 6 - 12% of the total weight of the mini-tablets, wherein the coating
30    comprises of 70 - 80% of a water insoluble polymer and 20 - 30"/o a water soluble polymer.

5.    An extended release fOrmulation of venlafaxine hydrochloride according to preceeding claims, wherein the water insoluble polymer used is selected from ethyl cellulose and eudragit
5

6.    An extended release formulation of veulsfaxine hydrochloride according to claim 5, wherein water insoluble polymer used is eihyl cellulose.

7.  An  extended  release  formulation  of  venla.faxine  hydrochloride  according  to

10    preceeding claims, wherein the water soluble component used is copolyvidonium.

8.    An extended release formulation of venlafaxine hydrochloride according to preceeding claims, wherein diameter of mini-tablet is from 3 - 6 mm.

15    9. An extended release formulation of venlafaxine hydrochloride according to pieceeding claims, which is administered once daily.

    I 0. A process for preparation of an extended release formulation comprising:
20    (i)    blending the venlafaxine hydrochloride and diluent,
    (ii)    granulating the blended ~ with an aqueous or non-aqueous solution of
        binder and drying it,
    (iil)   LU!Iiicliiing the dried granules and compressing into tablets,
    (iv)    Coating the  tablets  with an  aqueous  or non-aqueous  dispersion  of water

25    insoluble and water soluble component

(v)    Filling coated mini-tablets obtained in the step (iv) into capsules.
 

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