NZ609568B2 - Modified release pharmaceutical compositions of desvenlafaxine - Google Patents

Abstract

modified release pharmaceutical composition comprising Desvenlafaxine Benzoate (O-desmethylvenlafaxine benzoate), one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein Desvenlafaxine Benzoate is characterized by a powder X-ray diffraction pattern having peaks at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 ± 0.2 degrees. Also disclosed are specific modified release pharmaceutical compositions wherein concentration and AUC of the modified release composition are independent of food effect. having peaks at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 ± 0.2 degrees. Also disclosed are specific modified release pharmaceutical compositions wherein concentration and AUC of the modified release composition are independent of food effect.

Description

ED RELEASE PHARMACEUTICAL ITIONS OF DESVENLAFAXINE Field Of The Invention: This present invention relates to modified release pharmaceutical compositions comprising Desvenlafaxine and a process for ation thereof.

Background Of The Invention: Serotonin—norepinephrine reuptake inhibitors (SNRIS) are a class of antidepressant drugs used in the treatment of major depression and other mood disorders. They are also used to treat anxiety disorders, obsessive-compulsive disorder (OCD), attention deficit ctivity disorder (ADHD), chronic neuropathic pain. fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.

Serotoninenorepinephrine reuptake inhibitors (SNRIS) include but not limited to venlafaxine, Desvenlafaxine, milnacipran, tine, sibutramine, levomilnacipran and sibutramine.

Desvenlafaxine is nin—norepinephrine reuptake inhibitors and chemically, Desvenlafaxine is chemically named (i)- 1 irnethylamino)—1—(4- hydroxyphenyl)ethyljcyclohexanol, is a major metabolite of venlafaxine and has been shown to inhibit norepinephrine and serotonin uptake. Desvenlai'axine, which can also be referred to as O-Desmethylvenlafaxine or desmethylvenlafaxine, is represented by the following structural formula: (3:3 v" ‘ \- ~" - ¢.- Lil-g. , we" "wk "", "1.11.1".w" N‘w * "I 2' g 1 .«if ). a." l l ‘ "\V J 55"} \"r\ ./..«~"t O~desmethyl venlafaxine is a major metabolite of venlafaxine and has been shown to inhibit nephrine and serotonin uptake.

Desvenlafaxine was ified as a fumarate salt in US. Pat. No. 4.535,]86. However, the fumarate salt of O-desmethyl—venlafaxine has unsuitable physicochemical and permeability characteristics. O-desmethyl—venlafaxine is also exemplified as a free base in International Patent Publication No. WO 00/3255 5.

US. Pat. No. 6,673,838 disclose different crystalline forms of lafaxine Succinate mainly Form I, II, III and IV. Further it discloses amorphous form of Desvenlai‘axine ate. US. Pat. No. 7,820,716 discloses Form V and Form F of Desvenlafaxine Succinate.

Different salts of Desvenlafaxine have been disclosed in the literature. ate salt (US. Pat. No. 6,673,838 and US Patent ation No. 20040106576); formate (US.

Pat. No.7,001,920); hydrochloride (AU Patent Application No. 20080218997): e, maleate, mesylate, mandelate, quinic acid salt and tartrate (WO 2010008735); phosphate (WO 2009136756); D-glucuronate and orotate (WO 2009095431); oxalate, Benzoate and lactate (WO 3840); saccharinate (WO 2009017813).

Salt formation provides a means of altering the physicochemical and resultant biological teristics of a drug without modifying its chemical structure. A salt form can have a ic influence on the properties of the drug. The selection of a suitable salt is partially dictated by yield, rate and quantity of the crystalline structure. In addition, hygroscopicity, stability, solubility and the process profile of the salt form are important considerations. The fication of a salt form that exhibits a suitable combination of properties can be difficult.

The Succinate drate form of Desvenlafaxine has been incorporated into an extended release hydro-gel tablet, which reduces adverse effects such as nausea, vomiting, diarrhea, and abdominal pain. Formulations describing the use of hydroxypropyl methylcellulose (HPMC) as the hydrogel matrix have been described in US. Pat. No. 7,291,347.

WO 40577 US Patent Application No 20050175698 provides an enteric coated multiparticulate form of Desvenlafaxine that reduces rable characteristics associated with Desvenlafaxine and the hydrogel formulation thereof. These lafaxine multiparticulates are composed of Desvenlafaxine Succinate, Desvenlafaxine formate, or combinations thereof. Advantageously, this formulation also allows more convenient dosing to patients who have difficulty swallowing solid foods.

US Patent Application No 20100210719 describes stable ous O— desmethylvenlafaxine Succinate solid dispersions with one or more pharmaceutically acceptable carriers.

US Patent ation No 20100330172 discloses matrix controlled-release phannaceutical formulation comprising Desvenlafaxine Suceinate, having an MMD of n about 5 micrometer and about 100 micrometer and matrix rate—controlling pharmaceutically acceptable polymer.

US Patent Application No 20110046231 provides pharmaceutical composition comprising a solid state form of O—desmethylvenlafaxine salt and one or more pharmaceutically acceptable excipients, wherein the salt of ethylvenlafaxine is an oxalate salt, a Benzoate salt or a lactate salt.

US Patent Application No 20070014859 discloses ioavailable DVS (O— hylvenlafaxine Succinate) sustained release composition comprising a core containing at least DVS and a water insoluble filler in an oral dosage unit having a delayed release of at least about one hour and a ned release over multiple hours to provide a total e of greater than about 85% within about 12 to about 14 hours.

While there are many compositions available to reduce side effects of conventional dosage forms, still there remains a need to develop a controlled release composition of Desvenlafaxine.

Objective Of The Invention: The main object of invention is to provide modified release pharmaceutical composition of Desvenlafaxine.

W0 2012/140577 2012/051761 Another object of invention is modified release pharmaceutical composition comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable exeipientts) thereof.

Another object of invention is modified release pharmaceutical composition comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein d50 le size of lafaxine is upto about 80 microns.

Another object of invention is modified e pharmaceutical composition comprising Desvenlafaxine, one or more e modifying agent(s) and one or more pharmaceutically acceptable exeipient(s), wherein composition releases about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 0.9% NaCl in water at 100 rpm.

Another object of invention is modified release pharmaceutical composition comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein d50 particle size of Desvenlafaxine is upto about 80 microns such that composition releases about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 0.9% NaCl in water at 100 rpm.

Another object of invention is modified release ceutical composition comprises a matrix core comprising lafaxine, one or more release ing agent(s) and one or more pharmaceutically acceptable excipient(s) wherein the matrix core being further coated with one or more e modifying agent(s) and one or more phannaceutically acceptable exeipient(s).

Another object of invention is modified release pharmaceutical composition comprises a matrix core comprising lafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) wherein the matrix core being further coated with one or more release modifying agent(s) and one or more pharmaceutically acceptable exeipient(s), such that dso particle size of lafaxine upto about 80 microns.

WO 40577 PCT/IBZOIZ/051761 Another object of ion is modified release pharmaceutical composition ses a matrix core comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) n the matrix core being further coated with one or more release modifying agent(s) and one or more pharmaceutically acceptable ent(s) wherein composition es about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 0.9% NaCl in water at 100 rpm. r object of invention is modified release pharmaceutical composition comprises a matrix core comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) wherein the matrix core being further coated with one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein dso particle size of Desvenlafaxine is upto about 80 microns such that composition es about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 09% NaCl in water at 100 rpm.

Summary Of The Invention: The present ion provides modified release pharmaceutical compositions comprising lafaxine and a process for preparation thereof and their use in medicines. The invention relates to modified release pharmaceutical compositions comprising Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more pharmaceutically acceptable ent(s) thereof. which is bioequivalent to extended release composition of Desvenlafaxine Succinate in a bioavailability study in humans.

Further, Cmax and AUC of the modified release composition sing Desvenlafaxine Benzoate are independent of food effect.

Detailed Description Of The Invention: The present invention relates to provide modified release pharmaceutical composition of Desvenlafaxine and a process for preparation thereof.

It will be understood that, for the purposes of invention, Desvenlafaxine may be used in the form of base, pharmaceutically acceptable salt(s) or enantiomer(s) or polymorph(s) thereof.

The term "pharmaceutically acceptable salts" refers to salts comprise but not limited to which are prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, Suitable non~toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic. citric, sulfonic, formic, furnaric, gluconic, glutamic, romic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methane-sulfonic, mucic, nitric, . panlothenic, phosphoric, succinic, sulfuric. tartaric. p-toulenesufonic acids and the like. Preferably. lafaxine is in the salt form. More preferably Desvenlafaxine salt is te, Succinate, glutarate & palmitate.

In another ment, Desvenlafaxine Benzoate is in crystalline form or in amorphous form or a mixture thereof. It is to be understood for thc purposc of invention that Desvenlafaxine Benzoate may be present in the form of solvates with organic ts like ethanol, isopropanol or hydrate like monohydrate, dihydrate or enantiomers.

It is to be understood for the purpose of invention, Desvenlfaxine Benzoate can be prepared by methods disclosed in Indian Patent Application no. 0761/KOL/2011 are hereby orated in its ty.

In another embodiment, Desvenlafaxine Benzoate is in crystalline form terized by a powder X-ray diffraction pattern having at least one peak at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 i 0.2 degrees 29 substantially as depicted in Figure 1.

In another embodiment, Desvenlafaxine Benzoate is in crystalline form characterized by a powder X-ray ction pattern having peaks at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 i 0.2 degrees 26 substantially as depicted in Figure 1.

In another embodiment, Desvenlafaxine Benzoate is in crystalline form terized by a powder X-ray diffraction pattern having peaks at about 5.4, 9.5, 10.75, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 23.32 i 0.2 degrees 29 substantially as depicted in Figure 1.

W0 2012/140577 In another embodiment, Desvenlafaxine Benzoate is in lline form characterized by a powder X~ray diffraction n ntially in accordance with Figure 1.

More preferably, Desvenlafaxine te is in crystalline form characterized by a powder X—ray diffraction pattern having peaks at about 5.4, 9.5, 10.7, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 21.5, 23.3, 24.9, 28.3, 29.9 i 0.2 degrees 29.

Desvenlafaxine Benzoate has solubility in water of greater than 30mg/ml, preferably the s lity of the Desvenlafaxine Benzoate is at least about 50 mg/ml at 250 C, more preferably, the aqueous solubility of Desvenlafaxine Benzoate is about 60 mg/ml at ° c.

Desvenlafaxine Succinale has solubility in water of greater than 30mg/ml, ably the aqueous solubility of the Desvenlafaxine Succinate is about 35 mg/ml at 250 C.

Desvenlafaxine used in ceutical itions of invention in an amount of which is safe, well tolerated in patients with acceptable adverse effect profiles and are those in common practice and known to person skilled in the art.

Desvenlafaxine used to treat or prevent central nervous system disorders including, but not limited to sion ding but not limited to major depressive disorder, bipolar disorder and dysthymia), fibromyalgia, anxiety, panic disorder, agorophobia, post traumatic stress disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome), attention t disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, generalized anxiety er, autism, schizophrenia, obesity, anorexia a, bulimia nervosa, Gilles de la Tourette Syndrome, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction, (including premature ejaculation), borderline personality disorder, chronic fatigue syndrome, incontinence (including fecal incontinence, overflow incontinence, passive incontinence, reflex incontinence, stress urinary incontinence, urge incontinence, urinary exertional incontinence and urinary incontinence), pain (including but not limited to migraine, chronic back pain, phantom limb pain, central pain, neuropathic pain such as diabetic neuropathy, and postherpelic neuropathy), Shy Drager can also be used for preventing relapse or recurrence of depression; to treat ive impairment; for the inducement syndrome, Raynaud's syndrome, Parkinson's Disease, epilepsy, and others. Compounds and compositions of the present ion of cognitive enhancement in patient suffering from senile dementia, Alzheimer’s disease, memory loss, amnesia and amnesia syndrome; and in regimens for cessation of smoking or other tobacco uses.

The dosage amount useful to treat, prevent, inhibit or alleviate each of the aforementioned conditions will vary with the severity of the condition to be treated and the route of administration. The dose and dose frequency will also vary according to age, body weight, response and past l y of the individual human t.

Dosage is described in terms of the free base and is adjusted accordingly for the phamiaceutically acceptable salts. ln managing the t, is generally preferred that the therapy be ted at a lower dose and increased if necessary. s for non-human patients can be adjusted accordingly by one skilled in the art, A modified e pharmaceutical composition according to the invention comprises but is not limited to s (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets, and timed release s), pellets, beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules, microspheres, matrix formulations, microencapsulation.

The term "modified release" used in pharmaceutical compositions of invention means controlled release, extended release, sustained release, d e or combination of any of these techniques. In other words, modified release pharmaceutical composition of inventions may be any formulation technique wherein release of the active substance from the composition is modified to occur at a slower rate than that from an immediate release composition.

In one embodiment, a ed e pharmaceutical composition comprising Desvenlafaxine, one or more release modifying agent(s) and one or more phannaceutically acceptable excipient(s) thereof.

In another embodiment, a modified release pharmaceutical composition comprising Desvenlafaxine Succinate, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipients(s) thereof.

In another embodiment, a modified release pharmaceutical composition comprising Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more ceutically acceptable ent(s) thereof.

In another embodiment, a modified release pharmaceutical composition comprising crystalline form of Desvenlafaxine te, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) thereof.

In another embodiment, a modified release pharmaceutical composition sing crystalline form of Desvenlafaxine Benzoate Characterized by a powder X-ray diffraction 1.5 pattern having at least one peak at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 i- 0.2 degrees 29 substantially as depicted in Figure 1. one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) thereof.

In another embodiment, a modified e pharmaceutical composition comprising crystalline form of Desvenlafaxine Benzoate terized by a powder X—ray diffraction pattern having peak at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 i 0.2 degrees 20 substantially as depicted in Figure 1, one or more release modifying agent(s) and one or more pharmaceutically able excipient(s) thereof.

In another embodiment, a modified e pharmaceutical ition sing crystalline form of Desvenlafaxine Benzoate characterized by a powder X-ray diffraction pattern having peaks at about 5.4, 9.5, 10.75, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 23.32 i 0.2 degrees 20 substantially as depicted in Figure 1, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) thereof.

PCT/182012/051761 In another embodiment, a modified release pharmaceutical composition comprising crystalline form of Desvenlafaxine Benzoate characterized by a powder X—ray diffraction pattern substantially in accordance with Figure 1, one or more release modifying s) and one or more pharmaceutically acceptable excipient(s) f.

In another ment, a modified release pharmaceutical composition sing Desvenlafaxine Benzoate in crystalline form characterized by a powder X—ray diffraction pattern having peaks at about 5.4, 9.5, 10.7, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 21.5, 23.3, 24.9, 28.3, 29.9 i 0.2 degrees 20, one or more release modifying agent(s) and one or more pharmaceutically able excipient(s) thereof.

In another embodiment, a modified release pharmaceutical composition comprising amorphous form of Desvenlafaxine te, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) thereof.

In another embodiment, a modified release pharmaceutical composition comprising Desvenlafaxine ate, one or more release modifying agent(s) and one or more pharmaceutically able excipientts) thereof.

In another embodiment, a modified release pharmaceutical composition comprising Desvenlafaxine palmitate. one or more release modifying agent(s) and one or more pharmaceutically able excipient(s) thereof.

The rel ease modifying agent(s) is hydrophilic, hydrophobic or combinations f.

In another embodiment, a modified release pharmaceutical composition comprises lafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) thereof wherein release modifying agent(s) is from about 1 % to about 95 % based on total weight of composition.

In another embodiment, a modified release pharmaceutical composition comprises Desvenlafaxine Succinate, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) thereof wherein e modifying agent(s) is present in an amount less than about 55% based on total weight of composition.

In another embodiment, a ed release pharmaceutical composition comprises Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more phannaceutically acceptable excipient(s) thereof wherein release modifying agent(s) is from about I % to about 95 % based on total weight of composition.

The hydrophilic release modifying agent(s) according to invention comprises but not limited cellulose derivatives, alginic acid derivatives, polysaccharides. alkylene oxides or mixtures thereof.

Preferably, hydrophilic release ing agent(s) comprises oses or their salts or derivatives thereof, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hyprornellose), sodium carboxymethyl cellulose, alginic acid or their salts and derivatives thereof, er (Carbopol(TM)), polyethyleneoxide, xanthan gum, guar gum, locust bean gum, poly Vinyl e, polyvinyl alcohol, lactose.

The hydrophobic release modifying agent(s) according to the invention comprises but not limited to hydrogenated vegetable oils, polymethacrylates, ethyl cellulose or mixtures thereof. ably, hydrophobic release modifying agent(s) comprises Ammonio methacrylate copolymers type A and B as described in USP, methacrylic acid copolymer type A, B and C as described in USP, Polyacrylate dispersion 30% as described in Ph. Eur., Polyvinyl acetate dispersion, ethylcellulose, ose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate te, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), utyl rylate), poly(isobutyl methacrylate), and poly(hexyl rylate). Poly(isodecyl ryl ate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl te), poly(isopropyl acrylate), poly(isobutyl actylate), poly(octadecyl acrylate), waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl l; cetyl alcohol and myristyl alcohol; and fatty acid esters such as glyceryl earate, glycerol distearate; glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, yl palmitostearate, glyceryl behenate, and hydrogenated castor oil.

The average particle size of the les of Desvenlafaxine or a pharmaceutically acceptable salt thereof, in the ed release pharmaceutical composition of the invention is between about 5 microns to about 120 microns, preferably between about 7 microns to about 100 s and more preferably about 10 microns to about 80 microns.

The terms "average particle size", "dso" and "mass mean diameter" can be used interchangeably.

The average particle size, i.e. the average equivalent er, is defined as the diameter where 50 mass % of the particles of the Desvenlafaxine have a larger lent diameter, and the other 50 mass—% have a smaller equivalent diameter.

The "average particle size" also refers to the median particle diameter based on mass (i.e. the particle diameter where one half of the mass of les is buted by les with a lesser diameter and one half of the mass of particles is contributed by particles with a r diameter).

The particle size can be measured using various ly available methods such as measurement using light (eg. light—scattering methods or turbidimetric methods), sedimentation methods (eg. pipette analysis using an Andreassen pipette, sedimentation scales, photo—sedimentometers or sedimentation in a centrifugal force), pulse methods (eg. Coulter counter), or sorting by means of gravitational or centrifugal force.

It is to be understood for the purpose determining particle size of Desvenlafaxine or pharrnaceutically acceptable salts like Succinate or Benzoate in pharmaceutical compositions, the methods comprising but not limited to ing, crushing, extracting, separating and precipitating can be commonly employed. Determining particle size of Desvenlafaxine or pharmaceutically acceptable salts like Succinate or Benzoate in pharmaceutical compositions is well Within the scope of present invention.

In another embodiment, a modified e ceutical composition comprising Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein dso particle size of Desvenlafaxine is upto about 80 microns.

In another embodiment, a modified release ceutical composition comprising Desvenlafaxine te, one or more release modifying agent(s) and one or more pharmaceutically able excipient(s), wherein dso particle size of Desvenlafaxine te is from about 10 microns to about 80 microns.

In another embodiment, a modified release pharmaceutical composition comprising Desvenlafaxine Succinate, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein dso particle size of Desvenlafaxine Succinate is upto about 80 microns.

In another ment, a modified release pharmaceutical composition comprising Desvenlafaxine Succinate, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein (150 particle size of Desvenlafaxine Succinate is upto about 50 microns.

In another embodiment, a modified release pharmaceutical composition comprises a matrix core comprising Desvenlafaxine, one or more release ing agent(s) and one or more pharmaceutically acceptable excipient(s) wherein the matrix core being further coated with one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s).

In another embodiment, a modified release pharmaceutical composition ses a matrix core comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) wherein the matrix core being further coated with one or more release ing s) and one or more pharmaceutically able excipient(s), such that dso particle size of Desvenlafaxine is upto about 80 microns.

In another embodiment, a modified e ceutical composition comprises a matrix core comprising Desvenlafaxine, one or more release modifying agent(s) and one or more ceutically acceptable excipient(s) wherein the matrix core being further coated with one or more release modifying agent(s) and one or more pharmaceutically W0 2012/140577 acceptable excipient(s), wherein release of Desvenlafaxine is predominantly ed by coating.

In another embodiment, a modified release pharmaceutical ition having e of lafaxine in two or more steps at different release rates, which comprises a) a modified release part A comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable ent(s) and b) a modified release part B comprising lafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s).

In another embodiment, a modified release pharmaceutical composition having release of Desvenlafaxine in two or more steps at different release rates, which comprises a) a modified release part A comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically able excipient(s) and b) a modified release part B comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) wherein part A is coated with part B.

In another embodiment, a modified release pharmaceutical composition is bi—layer tablet comprises a sustained release layer comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s); and immediate release layer comprising lafaxine and one or more pharmaceutically acceptable excipient(s).

In another ment, a modified release pharmaceutical composition is multi-layered tablet. ln another embodiment, a modified release pharmaceutical composition comprises a inert core which is loaded with drug layer comprising Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) wherein Desvenlafaxine Benzoate layer being further coated with one or more e ing layer comprising e modifying agent(s) and one or more pharmaceutically acceptable excipient(s).

In another embodiment, a modified e pharmaceutical composition comprises a inert 3O core which is loaded with drug layer comprising Desvenlafaxine Succinate, one or more release modifying s) and one or more pharmaceutically acceptable excipient(s) 2012/051761 wherein Desvenlafaxine Succinate layer being further coated with one or more release modifying layer comprising release modifying agent(s) and one or more pharmaceutically acceptable ent(s).

The inert core comprises but not limited to sugar sphere or pellets, rystalline cellulose sphere, sugar/starch core or any suitable al.

In another embodiment drug layer and release ing layer may be separated by one or more separating layers.

The ting layer comprises one or more pharmaceutically acceptable excipients and one or more hydrophilic agent(s), hydrophobic agent(s) or combination thereof.

The hilic agent(s) according to ion comprises but not limited to cellulose derivatives, alginic acid derivatives, polysaccharides, alkylene oxides or mixtures thereof.

Preferably, hydrophilic s) comprises celluloses or their salts or derivatives thereof, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), sodium carboxymethyl cellulose, c acid or their salts and tives thereof, carbomer (Carbopol(TM)), polyethyleneoxide, xanthan gum, guar gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol, lactose.

The hydrophobic agent(s) according to the invention comprises but not limited to hydrogenated vegetable oils. polymethacrylates, ethyl ose or mixtures thereof.

Preferably, hydrophobic agent(s) comprises Ammonio methacrylate copolymers type A and B as described in USP, methacrylic acid copolymer type A, B and C as described in USP, Polyacrylate dispersion 30% as described in Ph. Eur., Polyvinyl e sion, ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly(hexyl methacrylate).

Poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), iethyl acrylate), poly(isopropyl acrylate), poly(isobutyl actylate), poly(octadecyl acrylate), waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol and myristyl 2012/051761 alcohol; and fatty acid esters such as glyceryl monostearate, glycerol distearate; glycerol monooieate, ated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated castor oil.

The term ‘pharmaceutically able ent(s)’ used in pharmaceutical compositions of invention comprise but not limited to diluents, binders, pH stabilizing agents, disintegrants, surfactants, glidants and lubricants.

The s of excipient(s) employed will depend upon how much active agent is to be used. One ent(s) can perform more than one function. s as used in the invention comprises but are not limited to, starches such as potato starch, wheat starch. corn starch: microcrystalline cellulose such as products known under the registered trademarks Avicei, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, ne, syrup, polyethylene oxide, polyvinyl pyrrolidone, poiy—N—vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and mixtures f.

Fillers or diluents, as used in the invention comprises but not limited to confectioner’s sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, l, sorbitol, talc, microcrystalline ose, calcium carbonate, m phosphate dibasic or tribasic, calcium sulphate, and the like can be used, Lubricants as used in the invention comprises but not limited to Mg, Al ,Ca or 7.n stearate, polyethylene glycol, yl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.

Glidants comprises but not d to, silicon dioxide; magnesium icate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.

Disintegrants comprises but not limited to starches; clays; celluloses; alginates; gums; cross—linked polymers, e.g., cross—linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL, cross—linked sodium carboxymethylcellulose or rmellose sodium, e.g., AC—Dl-SOL from FMC; and cross~linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum. Use of disintegrant according to the invention tates in the e of drug in the latter stage and thereby completely releasing the drug from the dosage form.

The pharmaceutical composition may optionally contain a surface—active agent. The preferred agent is rners composed of a central hydrophobic chain of polyoxypropylene (poly (propylene oxide» and polyoxyethylene (poly (ethylene oxide» that is well known as poloxamer. However, other agents may also be employed such as dioctyl sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS), polyoxyethylene sorhitan and poloxalkol derivatives, quaternary ammonium salts or other pharmaceutically acceptable surface-active agents known to one ordinary skilled in the art, The pharmaceutical composition can be formed by s processes known in the art but not limited to such as by dry granulation, wet ation, melt granulation, direct compression, double compression, ion spheronization, layering and the like. The solvent(s) used in wet granulation include all the solvents well known in the art or the es thereof.

In another embodiment, a modified pharmaceutical composition of invention comprises one or more coating comprising but not limited to modified release coating, sustained release coating, extended e coating, enteric coating, partial enteric coating or leaky enteric coating, bioadhesive coating and similar coatings known in the art. These coatings may help the pharmaceutical composition to release the drug at and for the required time.

These gs comprise coating s) selected from hydrophilic or hobic agent(s) or the combinations thereof.

The hydrophobic agent(s) in the coating comprises but not limited to Ammonio 3O methacrylate copolymers type A and B as described in USP, methacrylic acid copolymer type A, B and C as bed in USP, Polyacrylate dispersion 30% as described in pH.

Eur" Polyvinyl acetate dispersion, ethylcellulose, ose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate te; cellulose acetate phthalate, cellulose tn'acetate, ethy1 methacrylate), poly(ethyl methacrylate), poly(butyl rylate), poly(isobutyl methacrylate), and poly(hexyl methacrylate). Poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobuty1 actylate), poly(octadecyl acrylate), waxes such as beeswax, carnauba wax, rystalline wax, and ite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty acid esters such as glyceryl monostearate, glycerol distearate; glycerol eate, ated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated castor oil.

The hilic agent(s) in the coating comprises but not limited to celluloses or their salts or derivatives thereof, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), sodium carboxymethyl cellulose, alginic acid or their salts and derivatives thereof, carbomer (Carbopol(TM)), polyethyleneoxide, xanthan gum, guar gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol, lactose, PVA these hydrophilic polymers also act as pore forming agent.

These g ses one or more excipients selected from the group comprising coating , opacifiers, taste~masking agents, fillers, polishing agents, colouring agents, antitacking agents and thc like.

The pharmaceutical composition can be coated by a wide y of methods. Suitable methods include compression coating, coating in a fluidized bed or a pan and hot melt (extrusion) coating. Such methods are well known to those skilled in the art.

In another embodiment, a stable ed release pharmaceutical composition comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) thereof.

WO 40577 In another embodiment, a ed e pharmaceutical composition comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein composition releases about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 0.9% NaCl in water at l00 rpm.

In another embodiment, a ed release ceutical composition comprising Desvenlafaxine Succinate, one or more release modifying agent(s) and one or more phannaceutically acceptable excipient(s), n composition releases about 75% of Desvenlafaxine Succinate in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 0.9% NaCl in water at 100 rpm.

In another embodiment, a modified e pharmaceutical composition comprising Desvenlafaxine, one or more release modifying agent(s) and one or more phannaccutically acceptable excipient(s), wherein dsu particle size of Desvenlafaxine is upto about 80 microns such that composition releases about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 0.9% NaCl in water at 100 rpm.

In another embodiment, a modified e ceutical composition comprising Desvenlafaxine Benzoate, one or more release modifying s) and one or more pharmaceutically acceptable excipient(s), wherein dso particle size of Desvenlafaxine Benzoate is from about 5 microns to about 80 microns such that composition releases about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution tus in 900 ml of 0.9% NaCl in water at 100 rpm. in another embodiment, a modified release pharmaceutical composition comprises from about 10 % to about 50% by weight of lafaxine Succinate and less than about 60 % of release modifying agent(s) based upon total weight of composition, wherein dso le size of Desvenlafaxine Succinate is upto about 50 microns such that composition releases about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 0.9% NaCl in water at 100 rpm.

In another embodiment, a modified release pharmaceutical composition comprises a 3O matrix core comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) wherein the matrix core being further PCT/IBZOIZ/051761 coated with one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) wherein composition releases about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 0.9% NaCl in water at 100 rpm.

In another embodiment, a modified release pharmaceutical composition comprises a matrix core comprising Desvenlafaxine, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) wherein the matrix core being r coated with one or more e modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein dsg le size of Desvenlafaxine is upto about 80 microns such that composition releases about 75% of Desvenlafaxine in 16 hours measured using USP Type I dissolution apparatus in 900 ml of 0.9% NaCl in water at 100 rpm.

In another embodiment of the invention is a method of lowering the incidence of nauseau, vomiting, ea, abdominal pain, headache, vaso—vagal malaise, and/or trismus resulting from the oral administration of venlafaxine, Desvenlafaxine, or a salt of Desvenlafaxine other than iafaxine Benzoate to a patient. The method includes orally administering to a patient in nccd thereof a therapeutically effective amount of Desvenlafaxine Benzoate.

In another ment of the invention is a method of lowering the incidence of nausea, vomiting, diarrhea, abdominal pain, he, vaso—vagal malaise, and/or trismus resulting from the oral administration of Desveniafaxine te to a patient. The method includes orally administering to a patient in need thereof a therapeutically effective amount of a sustained release oral dosage form comprising Desvenlafaxine Benzoate having a peak blood plasma level of less than about 225 ng/ml.

Desvenlafaxine Benzoate may also be ed in combination with venlafaxine. The dosage of venlafaxine is preferably about 75 mg to about 350 mg/day and more preferably about 75 mg to about 225 mg/day. Still more preferably the dosage of venlafaxine is about 75 mg to about 150 mg/day. The ratio of Desvenlafaxine to 2012/051761 venlafaxine will vary from patient to patient depending upon a t‘s response rate, but generally will be at least 6:1 Desvenlafaxine to venlafaxine.

Desvenlafaxine Benzoate is less fluffy than that of Desvenlafaxine Succinate. So, the dusting is less during manufacturing of the drug product and which gives ease of handling the drug nce as compared to the Succinate and there is a minimum chance of drug loss during manufacturing process and hence gives an advantage over Succinate salt.

Further, the particle size distribution of Desvenlafaxine Benzoate drug substance is smaller as compared to Desvenlafaxine Succinate drug substance. Hence, the distribution of drug nce in the drug product is uniform and gives no chance of variation in content uniformity of the final drug product/dosage form.

Due to its advantegeous properties, lower concentration of rate controlling polymers or release modifying rs is required for Desvenlafaxine Benzoate as compared to Desvenlafaxine Succinate in matrix tablet formulation to achieve the similar drug e profile and also to make the bioequivalent product with q®.

Pristiq® is the brandname for the extended release composition of Desvenlafaxine Succinate 50 mg and 100 mg marketed by Wyeth Pharmaceuticals Inc. (Now Pfizer) Philadelphia, PA 19101.

In another embodiment, a modified release pharmaceutical composition comprising Desvenlafaxine Benzoate, one or more release modifying s) and one or more pharmaceutically acceptable excipient(s), wherein the modified release composition provides Cmax (peak plasma levels) of upto about 225 ng/ml.

In another ment, a modified release pharmaceutical composition comprising Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s), wherein the modified release composition provides C"lax (peak plasma levels) of upto about 300 ng/ml.

In another embodiment, a ed release pharmaceutical composition comprising Desvenlafaxine Benzoate, one or more release ing agent(s) and one or more pharmaceutically acceptable excipient(s) f, n Cmax and AUC of the modified 2012/051761 release composition are within the limit of 80 % to 125 % of Cmax and AUC of the extended release composition of Desvenlafaxine Succinate.

The term "Cm" as used , means maximum plasma concentration of Desvenlafaxine produced by the ingestion of the modified release composition of invention or the marketed I’ristiq® (Extended Release Composition of Desvenlafaxine Succinate) ition. Cmax or peak plasma level may be used interchangeably.

The term "AUC" as used herein, means area under the plasma concentration—time curve of Desvenlafaxine produced by the ingestion of the modified e composition of ion or the marketed Pristiq® (Extended Release Composition of Desvenlafaxine Succinate).

In another embodiment, a modified release pharmaceutical composition comprising Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more pharmaceutically able excipient(s) thereof wherein, Tmax of the modified release composition is comparable to Tmax of the extended release composition of Desvenlafaxine Succinate.

The term "me" as used herein, means time to the maximum observed plasma concentration of Desvenlafaxine produced by the ingestion of the modified release composition of invention or the marketed Pristiq® (Extended Release Composition of Desvenlafaxine Succinate).

In another embodiment, a modified release ceutical composition comprising Desvenlafaxine Benzoate, one or more e modifying agent(s) and one or more pharmaceutically acceptable excipient(s) thereof wherein, Tmax of the ed release composition is less than about 8 hours.

In r embodiment, Cmax and AUC were comparable for the ed release composition of Desvenlafaxine Benzoate when administered after a high—fat meal and under fasting condition as the ratios falls between 80-125%.

PCT/132012/051761 In another embodiment, a modified release pharmaceutical composition comprising Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more ceutically acceptable excipient(s) thereof wherein CW, and AUC of the modified e composition are independent of food effect.

In another embodiment, a modified release pharmaceutical composition comprising Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more pharmaceutically acceptable excipient(s) thereof, which is bioequivalent to Pristiq® tablet in a bioavailability study in humans.

A modified release pharmaceutical composition of the present invention can be used to treat or prevent central nervous system disorders including, but not limited to depression (including but not limited to major depressive disorder, bipolar disorder and dysthymia), fibromyalgia, anxiety, panic disorder, agorophobia, post traumatic stress disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome), ion deficit disorder (with and without ctivity), obsessive compulsive disorder (including trichotillomania). social anxiety disorder, lized anxiety disorder, autism, schizophrenia, obesity, anorexia a, bulimia nervosa, Gilles de la Tourette Syndrome, vasomotor g, cocaine and alcohol addiction, sexual ction, (including premature ejaculation), borderline personality disorder, chronic fatigue me, incontinence (including fecal incontinence, overflow incontinence, passive incontinence, reflex inence, stress urinary inence, urge incontinence, urinary exertional incontinence and urinary incontinence), pain (including but not limited to ne, chronic back pain, phantom limb pain, central pain, ncuropathic pain such as diabetic neuropathy, and postherpetic neuropathy), Shy Drager can also be used for preventing relapse or recurrence of depression; to treat cognitive impairment; for the inducement me, Raynaud's syndrome, Parkinson's Disease, epilepsy, and .

Compounds and compositions of the present invention of cognitive enhancement in patient suffering from senile dementia, mer‘s disease, memory loss. amnesia and amnesia syndrome; and in regimens for cessation of smoking or other tobacco uses.

Additionally, compounds and itions of the t invention can be used for 3O treating hypothalamic amenorrhea in depressed and pressed human females.

The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this ion in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present sure, and the accompanying claims.

X —RD Stability Study The X-ray diffraction pattern for Desvenlafaxine Benzoate was measured using X-ray ctometer.

X—RD pattern for Desvenlafaxine Benzoate is depicted in Figure 1.

Example 1: S.N6 NAME or INGREDIENTS % _Intragranular IDibasic calcium phosphate/ 18 12 rystalline Cellulose NF Film Coatin- nPurified Water USP/ IPA/DCM - Procedure: 1. Aqueous/Non-aqueous granulation of Desvenlafaxine Benzoate, Hyprornellose and Dibasic calcium phosphate/ MCC using Povidone as binder.

Dry the granules at SOi-S°C till desired LCD is ed.

@PP’N Add the ranular part and mix well.

Compress the granules using suitable punch tooling Aqueous /Non—aqueous film coating.

WO 40577 Example 2: S.NO. NAME OF INGREDIENTS % W/W H lafaxine Benzoate 36.58 Hypromeliose 20.00 Purified Water/IPA -s Dibasic calcium phosphate/ Microcrystalline Cellulose 17 82 Extra_ranular ll Magnesium Stearate/Stearic Acid 2.00 Release Modif in Coatin Hypromellose Ethyl cellulose 1 I IPA/DCM Film Coatin_ 13 Purified WaterUSP/IPA/DCM Procedure: 1. Aqueous /Non-aqueous granulation of Desvenlafaxine Benzoate, Hypromellose and Dibasic calcium ate/ MCC using Povidone as binder.

!J Dry the granules at 50i5°C till desired LCD is achieved Add the Extragranular part and mix well.

Compress the granules using suitable punch tooling U! Non— s coating with a build up of 1—10%w/w.

Aqueous /Non-aqucous film coating.

Example 3: NAME OF IENT % W/W Intragranular Extra_ranular nHypromellose 18.30 dal Silicon Dioxide 3.00 Film Coating nOpadry 2.50 Purified Water USP/ IPA/DCM ‘33 Procedure: 1. s /N0n-aqueous granulation of Desvenlafaxinc Glutarate/Palmitate, Hypromellose and Dibasic calcium phosphate / MCC using Povidone as binder. 95‘8"?) Dry the granules at SOiS°C till desired LOT) is achieved.

Add the Extragranular part and mix well.

Compress the granules using suitable punch toolingl Aqueous /Non-aqueous film coating.

Example 4: Immediate release layer Desvenlafaxine Benzoate .Purified Water Dibasic calcium phosphate /1Microcrystalline— Cellulose Colloidal Silicon Dioxide — Sustained release layer 7 Desvenlafaxine Benzoate 3170 il or Ethylcellulose 2500 ed Water Dibasic calcium phosphate / rystalline 1356 Cellulose Colloidal Silicon Dioxide 2.00 Film Coating Opadry 50 14 Purified Water USP/ IPA/DCM Procedure: Immediate release layer 1. Aqueous iNon-aqueous granulation of Desvenlafaxine Benzoate and c calcium phosphate/ MCC using Povidone as binder. 2012/051761 2. Dry the granules at 50i5°C till d LOD is achieved. 3. Add Colloidal Silicon Dioxide and ium stearate and mix well.

Sustained release layer 1. Aqueous/Non—aqueous granulation of Desvenlafaxine Benzoate, Dibasic calcium phosphate / MCC using Methacrylic acid or Ethylcellulose as ned release polymer. 2. Dry the granules at 50i5°C till desired LOD is achieved 3. Add Colloidal Silicon Dioxide and Magnesium stearate and mix well. 4. Compress both the layers of Immediate and Sustained release part using suitable punch tooling.

U1 . Aqueous /Non—aqueous film coating.

Example 5: Film Coating ied Water USP/ IPA/DCM Procedure: 1. Desvenlafaxine Succinate and Hypromellose or Xanthum gum are dry mixed. 2. Add Microcrystalline Cellulose / Dibasic calcium phosphate to step 1 and mix well. 3. Add Colloidal Silicon Dioxide to Step 3 and mix well. 4. Lubricate the blend with Stearic acid or Magnesium Stearate.

. Compress the granules using le punch tooling. 6. Aqueous {Non—aqueous film coating.

Example 6: NAMEOFINGREDIENTS % —Intragranular II-Microelystalline Cellulose_xtra;lanula1 II—I Release Modif1n_ Coatin; mellose -O5 Ethyl cellulose 1 1 IPA/DCM -S Film Coatin Purified Water USP/ IPA/DCM Procedure: 1. Aqueous queous granulation of Desvenlafaxine Succinate, Hypromellose and Dibasic calcium phosphate/ MCC using Povidone as binder. 2. Dry the es at 50i5°C till desired LOD is achieved. 3. Add the Extragranular part and mix well, 4. Compress the granules using suitable punch tooling . Non- Aqueous coating with a build up of 1—10%w/w. 6. Aqueous queous film coating.

Example 7: NAME OF INGREDIENT % Desvenlafaxine ate Purified Water - Dibasic calcium phosphate / Microcrystalline 11.50 Cellulose -Colloidal Silicon Dioxide - Part-B Desvenlafaxine Succinate nEudiagit or Ethylcellulose nPurified Water Dibasic m phosphate / Microcrystalline 1356 Cellulose -Colloidal Silicon Dioxide W0 2012/140577 Opadry Purified Water USP/ lPA/DCM Procedure: Part A 1. Aqueous /Non-aqueous ation of Desvenlafaxine Succinate and Dibasic calcium phosphate/ MCC using Povidone as binder. 2. Dry the granules at SOiSOC till desired LOD is achieved. 3. Add Colloidal Silicon Dioxide and ium stearate and mix well.

Part B 4. Aqueous Non-aqueous granulation of Desvenlafaxine Succinate, Dibasic calcium phosphate / MCC using Methacrylic acid or ellulose as sustained release Dry the es at SOiSOC till desired LOD is achieved Add Colloidal Silicon Dioxide and Magnesium stearate and mix well.

Compress both the layers of Part A and Part B part using suitable punch tooling. 9°99?" Aqueous /Non-aqueous film coating.

Example 8: W0 2012/140577 Film Coating nOpadry —02 Purified Water USP/ M Procedure: 1. lafaxine Succinate and Ethyl Cellulose are dry mixed. 2. Add Microcrystalline Cellulose / Dibasic calcium phosphate to step 1 and mix well. 3. Add Colloidal Silicon Dioxide to Step 3 and mix well. 4. Lubricate the blend with Stearie acid or Magnesium Stearate.

. Compress the granules using suitable punch tooling. 6. Aqueous queous film coating.

Example 9:I SN NAMEoF INGREDIENT ugar Hardening I» DCM/IPA Total Urug Loading ure — 1. Hardening of sugar spheres carried out. 2. Mix Desvenlafaxine Succinate, HPMC, talc & Aerosil. 3. Coat the e of Step 2 on sugar spheres of step 1 using DCM/IPA solution to form drug layer. 4. Release Modifying coating of HPMC, ethyl cellulose, tale and triethyl citrate loaded on Drug layer of Step 3.

Example 10: WO 40577 Extragranular Microcrystalhne Cellulose Stcaric Acid _ a,ilm Coating v —(1.5 l Procedure: 1. ueous granulation of Desvenlafaxine Benzoate and Hypromellose using Povidone as binder. 2. Dry the granules at 55i5°C till desired LOD is achieved. 3. Add the Extragranular part and mix well. 4. Compress the granules using suitable punch tooling . Aqueous film coating. e 11: Eyedients Intragranular 1 Desvenlafaxine Succinate 2 Hypromellose Microcrystalline 1.52 Cellulose 6 Colloidal Siliconi'3. 6 il i i Film Coating Procedure: 1. Non—aqueous granulation of Desvenlafaxine Succinate and Hypromellose using Povidone as binder. weww Dry the granules at 55i5°C till desired LCD is ed Add the Extra granular part and mix well.

Compress the granules using suitable punch tooling Aqueous film coating.

Example 12: I——gInn'agranular lafaxine 36 24 Succinate I Hypromellose _3 570 Colloidal Silicon _ i l Ext;agr(mular r Colloidal ‘ Dioxide I _0.5.2.0 . n— ; Film Coating Opadry 2030 : Procedure: 1. Compact Desvenlafaxine Succinate, Hypromellose, Colloidal Silicon Dioxide, Talc and Magnesium te in a roller compactor. 9:953!" Sift and size the granules using comminuting mill to desired es size.

Add the Extragranular part and mix well.

Compress the granules using suitable punch tooling Aqueous film coating.

Example 13: -_edins" ' ' 7 7 Intragranular 1 Desvenlafaxine 3 7.56 ‘ Benzoatc 2 Hypromellose 000153000 rauulm I—w1644Cellulose flDioxide Film Coating ed water Procedure: 1. t Desvenlafaxine Benzoate, Hypromellose, Talc and Stearie Acid in a roller eompactor.

:PP’P Sift the granules using eomminuting mill to desired granules size.

Add the Extragranular part and mix well.

Compress the granules using suitable punch tooling . Aqueous film coating.

In-Vitro Dissolution Study: Table 1 given below shows the dissolution profile of Desvenlafaxine Benzoate Modified e Tablets of Example 1 of the present invention carried out in 900 ml of 0.9% NaCl in water for 24 hours using Apparatus USP-I t) at 100 rpm speed. The release profile (cumulative % of dmg released) is given in Table 1.

Table 1: umulative Drug Release For Example 1 -Not More Than 20% -Not Less Than 75% Table 2 given below shows the dissolution profile of Desvenlafaxine Suceinate Modified Release Tablets of Example 5 of the present invention carried out in 900 ml of 0.9% NaCl in water for 24 hours using Apparatus USP-I (Basket) at 100 rpm speed. The release profile (cumulative % of drug released) is given in Table I.

Table 2: Time In Hrs Cumulative % Drug Release For Example 5 Not More Than 20% "50% Not Less Than 75% In -Vivo Bioavailability Study: An Open Label, ed, Randomized, Single-Dose, Treatment, Sequence, Three—Period Crossover Oral Bioequivalenee Study Of Reference product (Treatment A) PRISTIQ® (Extended release composition of Desvenlafaxine Suceinate) 100 mg of Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 and Test product (Treatment B) Desvenlafaxine Benzoate Modified Release Tablet 100 mg ated as per Example 13 under fasting conditions and food effect study of Desvenlafaxine Benzoate Modified Release Tablet 100 mg formulated as per example 13 administered under fasting ment B) and fed (Treatment C) conditions in Healthy, Adult, Human Male Subjects.

The study was designed to demonstrate the r clinical cy compared to Pristiq®.

The ill-viva bioavailability study in fasting state shows the results as shown in the Table 3 below: Table 3: Comparative pharmacokinetic parameters of Example 13 vs Pristiq® 100 mg in Fasted state Tmax (hrs) ng. hr /ml 12g. hr /ml rig /mI ; lafaxine 5429.332 6140836 249.504 5.943 Benzoate MR s 100 mg 5762.351 263.630 6096.586 Conclusions: Bioequivalence between Treatment A and B administered under fasting ions: The 90% Confidence Interval of the relative geometric mean of Cum, AUC(0.[) and AUC(0- m) were found to be within the limit of 80 % to 125 %. Based on the results obtained, Desvenlafaxine Benzoate Modified Release Tablet 100mg formulated as per Example 13 and PRISTIQ® (Extended release composition of Dcsvenlafaxine Sueeinatc) 100 mg of Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101, are found to be bioequivalent in healthy human adult male subjects under fasting conditions.

Food effect (Treatment B vs C) on Desvenlafaxine Benzoate Modified Release Tablet 100mg: Administration of Desvenlafaxine Benzoate ed Release Tablets 100 mg with food had a minimal effect on drug absorption, ing in an approximate 2 hour delay in Tmax.

Cmm and AUC were comparable for Desvenlafaxine Benzoate Modified Release Tablets l00 mg when administered after 21 hi gh-fat meal and under fasting condition as the ratios falls between EEO-125%. Food is not expected to have significant clinical effect on the tion (Cmax and AUC) of Desvenlafaxine from lafaxine Benzoate Modified Release Tablets 100 mg. Desvenlafaxine Benzoate Modified Release Tablets 100 mg can be administered Without regard to food.

Claims (1)

1.CLAIMS 1. A modified release pharmaceutical composition comprising Desvenlafaxine Benzoate, one or more release modifying agent(s) and one or more pharmaceutically acceptable ent(s), wherein Desvenlafaxine Benzoate is characterized by a powder X—ray diffraction pattern having peaks at about 5.4, 10.75, 16.6, 18.0, 19.2, 23.32 i 0.2 degrees 26. The ed release pharmaceutical composition of claim 1, wherein Desvenlafaxine Benzoate is characterized by powder X—ray diffraction pattern having peaks at about 5.4, 9.5, 10.7, 16.1, 16.6, 17.3, 18.0, 19.2, 20.4, 21.5, 23.3, 24.9, 28.3, 29.9 i 0.2 degrees The modified release pharmaceutical composition of claim 1, n said composition releases about 75% of Desvenlafaxine in 16 hours measured using USP Type i dissolution tus in 900 ml of 0.9% NaCl in water, at 100 rpm. The modified release pharmaceutical composition of claim 1, wherein Cmax and AUC of the modified release composition are within the limit of 80 % to 125 % of Cmax and AUC of the extended release composition of lafaxine Succinate. ‘ The modified release pharmaceutical ition of claim . 1, n Cmax and AUC of the modified release composition are independent of food effect. A modified release pharmaceutical composition according to claim 1, substantially as herein described with reference to any one of the accompanying examples and or figure thereof. wo