This application is patent of addition of patent application No. 2667/DEL/2005 filed on Oct 5, 2005.
Field of the invention
The present invention relates to an extended release pharmaceutical composition comprising venlafaxine and pharmaceutically acceptable salts thereof and process for the preparation of said composition.
Background of the invention
Venlafaxine is an anti-depressant and acts by inhibiting synaptosomal uptake of norepinephrine (3H-NE) and serotonin (14C-5HT). Processes for the preparation of Venlafaxine hydrochloride are described in EP-A-112,669 and in Yardley et al., J. Med. Chem., 1990, vol. 33, page 2899.
Venlafaxine hydrochloride is available as an immediate release tablet or as an extended release capsule. Modified release dosage forms, such as extended release formulations, can deliver the drug within a safe and effective range over a longer period of time than a normal immediate release dosage form, thereby allowing for less frequent dosing. The ability to take a drug once a day instead of two or three times a day is a benefit to the patient in terms of convenience and also in terms of compliance. Indeed, a controlled release of the drug can in some cases provide superior efficacy and/or reduced side effects as the potential overdosing/under-dosing (i.e. blood plasma concentration peaks and troughs) of a multi-dose regimen are avoided.
US 6,274,171 and EP 797,991 relate to an extended release dosage form of venlafaxine hydrochloride. Specifically, an encapsulated dosage form is taught that comprises spheroids of venlafaxine hydrochloride, microcrystalline cellulose, and hydroxypropylmethylcellulose (HPMC). These spheroids are coated with a mixture of ethyl cellulose and HPMC.
WO 99/22724 discloses an encapsulated extended release venlafaxine formulation comprising spheroids substantially free of hydroxypropylmethylcellulose.
WO 94/27589 discloses an osmotic dosage form that delivers a drug by osmotic action over an extended period of time wherein the drug composition comprises venlafaxine and hydroxypropylalkylcellulose.
U.S. Pat. No. 6,048,547 discloses a sustained-release venlafaxine hydrochloride pharmaceutical composition where venlafaxine and microcrystalline cellulose are combined with polyethylene oxide (PEO) and compressed into tablets.
WO 04/091580 discloses coated pellets comprising a) a pellet core which comprises venlafaxine hydrochloride; b) a first coating which comprises a lipophilic layer or a sparingly water-soluble layer, and c) a second coating which comprises a water-insoluble polymer or polymer mixture. They disclose a process wherein process avoids the use of organic solvents during the coating step. They also disclose that pellet core and/or coating are free of polyvinylpyrrolidone.
Summary of the invention
We have now developed an alternative extended release pharmaceutical composition comprising plurality of beads comprising a core of venlafaxine or pharmaceutically acceptable salt thereof and the said core being coated with a mixture of ethyl cellulose and polyvinylpyrrolidone.
We have also developed an extended release pharmaceutical composition comprising plurality of beads comprising: extrudes or spheroids comprising venlafaxine or pharmaceutically acceptable salt thereof, spheronizing aid and binder and a coating comprising a mixture of ethyl cellulose and polyvinylpyrrolidone, wherein the extrudes or spheroids are prepared using an aqueous solvent.
Hence, according to one of the aspects, extended release pharmaceutical composition comprising plurality of beads comprising:
i) extrudes or spheroids comprising venlafaxine or pharmaceutically acceptable salt thereof, spheronizing aid and binder
ii) a coating comprising a mixture of ethyl cellulose and polyvinylpyrrolidone, wherein the extrudes or spheroids are prepared using an aqueous solvent.
According to another aspect, there is provided a process for preparation of an extended release pharmaceutical composition comprising plurality of beads comprising:
i) extrudes or spheroids comprising venlafaxine or pharmaceutically acceptable salt thereof, spheronizing aid and binder
ii) a coating comprising a mixture of ethyl cellulose and polyvinylpyrrolidone, wherein the extrudes or spheroids are prepared using an aqueous solvent.
According to another aspect, there is provided a method of treating or preventing depression, general anxiety disorder, social anxiety disorder and post traumatic stress disorder in a mammal in need thereof comprising administering to the mammal an extended release pharmaceutical composition comprising plurality of beads comprising:
i) extrudes or spheroids comprising venlafaxine or pharmaceutically acceptable salt
thereof, spheronizing aid and binder
ii) a coating comprising a mixture of ethyl cellulose and polyvinylpyrrolidone, wherein the extrudes or spheroids are prepared using an aqueous solvent.
According to another aspect, there is provided an extended release pharmaceutical
composition comprising plurality of beads comprising:
i) core comprising venlafaxine or pharmaceutically acceptable salt thereof
ii) a coating comprising a mixture of ethyl cellulose and polyvinylpyrrolidone.
The ratio of ethyl cellulose and polyvinylpyrrolidone may vary from 60:40 to 80:20.
According to another aspect, there is provided a process for preparation of an extended release pharmaceutical composition comprising plurality of beads comprising: i) core comprising venlafaxine or pharmaceutically acceptable salt thereof ii) a coating comprising a mixture of ethyl cellulose and polyvinylpyrrolidone.
According to another aspect, there is provided a method of treating or preventing depression, general anxiety disorder, social anxiety disorder and post traumatic stress disorder in a mammal in need thereof comprising administering to the mammal an extended release pharmaceutical composition comprising plurality of beads comprising: i) core comprising venlafaxine or pharmaceutically acceptable salt thereof ii) a coating comprising a mixture of ethyl cellulose and polyvinylpyrrolidone.
According to another aspect, there is provided an extended release pharmaceutical
composition comprising plurality of beads comprising: i) inert core
ii) drug layer comprising venlafaxine or pharmaceutically acceptable salt thereof iii) a coating surrounding the drug layer comprising a mixture of ethyl cellulose and polyvinylpyrrolidone.
According to another aspect, there is provided a process for preparation of an extended release pharmaceutical composition comprising plurality of beads wherein process comprises the steps of:
i) preparing a solution or dispersion of venlafaxine in a suitable solvent,
ii) spraying the above prepared dispersion onto the inert core and drying off the solvent
iii) preparing a solution or dispersion of mixture of ethyl cellulose and polyvinyl
pyrrolidone in suitable solvent iv) coating the beads obtained in step ii) with a polymeric solution or dispersion
obtained in step iii) and drying off the solvent v) optionally coating the beads obtained in step iv) with a non functional coating,
vi) compressing the beads into suitable size tablets or filling into capsules.
According to another aspect, there is provided an extended release pharmaceutical composition comprising plurality of beads comprising:
i) spheroids/extrudes comprising venlafaxine or pharmaceutically acceptable salt thereof ii) a coating surrounding the spheroids/extrudes comprising a mixture of ethyl cellulose and polyvinylpyrrolidone.
According to another aspect, there is provided a process for preparation of an extended release pharmaceutical composition comprising plurality of beads wherein process comprises the steps of:
i) preparing a solution or dispersion of binding agent in a suitable solvent,
ii) wetting venlafaxine hydrochloride with a solution or dispersion of binding agent,
iii) extruding and optionally spheronizing the mixture, drying and sieving,
iv) preparing a solution or dispersion of mixture of ethyl cellulose and polyvinyl pyrrolidone
in suitable solvent v) coating the extrude or spheroid of step iii) with a polymeric solution or dispersion
obtained in step iii) and drying off the solvent
vi) optionally coating the beads obtained in step v) with a non functional coating, vii) compressing the beads into suitable size tablets or filling into capsules.
According to another aspect, there is provided an extended release pharmaceutical
composition comprising plurality of beads comprising: i) inert spheroids/extrudes
ii) drug layer comprising venlafaxine or pharmaceutically acceptable salt thereof iii) a coating surrounding the drug layer comprising a mixture of ethyl cellulose and polyvinylpyrrolidone.
According to another aspect, there is provided a process for preparation of an extended release pharmaceutical composition comprising plurality of beads comprising wherein process comprises the steps of:
i) preparing a solution or dispersion of binding agent in a suitable solvent,
ii) wetting pharmaceutically acceptable inert excipients with a solution or dispersion of
binding agent,
iii) extruding and optionally spheronizing the mixture, drying and sieving, iv) preparing a solution or dispersion of venlafaxine in a suitable solvent, v) spraying the above prepared dispersion onto the extrudes/spheroids and drying off the
solvent vi) preparing a solution or dispersion of mixture of ethyl cellulose and polyvinyl pyrrolidone
in suitable solvent vii) coating the extrude or spheroid of step iii) with a polymeric solution or dispersion
obtained in step iii) and drying off the solvent
viii) optionally coating the beads obtained in step vii) with a non functional coating, ix) compressing the beads into suitable size tablets or filling into capsules.
Detailed description
The term venlafaxine as used herein refers to racemic mixture, of R and S-venlafaxine and their optically pure enantiomers. As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.
The term 'aqueous solvent' as used herein includes water or its mixture thereof with other organic solvents. The ratio of waterorganic solvent should be at least 90:10, particularly 95:5, more particularly aqueous solvent is water substantially free of organic solvent. Venlafaxine is more soluble in water than organic solvent, hence it is preferred solvent.
The term 'extended release pharmaceutical composition' as used herein includes any pharmaceutical composition that achieves the slow release of drug over an extended period of time, and includes both prolonged and sustained release compositions.
Composition as used herein includes tablets, capsules, pills, minitablets, sachet and the like.
Ethyl cellulose is an inert, hydrophobic polymer used extensively in a number of dosage forms. It has been used as a coating material for tablet and granules, as a tablet binder, in preparing microcapsules and microspheres and also as film forming and matrix forming material for sustained release dosage forms.
Ethyl cellulose is available in various grades varying in their viscosities and particle size. Various grades available are Ethocel standard premium 4, 7, 10, 20, 25, 45, 100 and Ethocel FP 7, 10, 100 wherein the number indicate the viscosity of 5% (w/w) of polymer solution in 80/20 toluene/alcohol at 25°C and FP indicates the fine particle grade of premium product.
Polyvinylpyrrolidone, also known as povidone, polyvidon, povidonum and PVP, is sold under the trade names Kollidon™ (BASF Corp.) and Plasdone™ (ISP Technologies). They are polydisperse macromolecular molecules, with a chemical name of 1-ethenyl-2-pyrrolidinone polymers and 1-vinyl-2-pyrrolidinone polymers. Povidone polymers are produced commercially as a series of products having mean molecular weights ranging from about 10,000 to about 700,000 daltons.
Polyvinylpyrrolidone have diverse roles in a pharmaceutical composition. It is used as a dispersing and suspending agent, and has been used as a tablet binder, coating agent, and viscosity-increasing agent in pharmaceutical preparations.
Plurality of beads include spheroids, extrudes or inert core. Extrudes/spheroids are prepared by extrusion/spheronization process.
The term 'inert core' as used herein includes water insoluble, soluble and swellable cores. Water insoluble core includes silicon dioxide, small particles of glass, or plastic resin particles such as polypropylene or polyethylene. Water-soluble core includes sugar spheres such as glucose, mannitol, lactose, xylitol, dextrose, sucrose and salt cores such as sodium chloride, potassium chloride. Water swellable core may be made up of hydroxypropyl methylcellulose, microcrystalline cellulose (Celphere®) or starch. Inert core may have a diameter ranging from about 150-600 urn, preferably about 250-425 urn.
Inert core or inert spheroid/extrude is coated with a drug layer comprising venlafaxine. Drug layer may further comprise binding agent to give proper adhesion of the drug layer to inert core. Binding agent includes water insoluble or soluble binding agent that are commonly known in the art such as hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, polymethacrylates or ethylcellulose.
Coating solution may be applied using techniques such as spray coating in a conventional coating pan or fluidized bed processor or dip coating. Solution or dispersion of polymers is prepared in solvents selected from dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixture thereof.
Drug layer coated beads/spheroids/extrudes are then coated with a coating composition comprising a mixture of ethyl cellulose and polyvinylpyrrolidone.
Coating solution may further comprise other pharmaceutically acceptable ingredients such as plasticizers, coloring agents and surfactants.
Examples of suitable plasticizers include acetyl triethyl citrate, dibutyl phthalate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, propylene glycol, triacetin, polyethylene glycol and diethyl phthalate.
The thickness and number of polymeric coating to be applied to give the desired release characteristics of the cores can vary widely and will depend on the particular polymer or mixture thereof chosen. This amount can be readily determined by one skilled in the art using dissolution profile data.
In another embodiment, the beads are processed into tablet dosage form by direct compression technique, comprising the steps of blending venlafaxine beads/extrudes/spheroids and pharmaceutically inert excipient; lubricating the blend; directly compressing the lubricated blend into suitable sized tablets and; optionally coating with film forming polymer and coating additives.
In another embodiment, the beads are processed into capsule dosage form comprising the steps of blending venlafaxine beads/extrudes/spheroids and pharmaceutically inert excipient; lubricating the blend and filling into suitable size capsules.
The term 'pharmaceutically acceptable inert excipients' as used herein includes all excipients used in the art of manufacturing solid dosage forms. Examples include binders, diluents, spheronization aid, surfactants, lubricants/glidants, coloring agents, and the like.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Spheronization aid, contributes to plasticity of the wet mass in-process while imparting strength to the finished pellet. Specific examples of spheronizing aid include microcrystalline cellulose, cellulose powder, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate and crosslinked polyvinyl pyrrolidone.
Specific examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.
Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like. Coloring agents include any FDA approved colors for oral use.
The tablet dosage form may optionally be coated with functional and/or non-functional layers comprising film-forming polymers, if desired.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of this invention in any way.
EXAMPLES
EXAMPLE 1

(Table Remove)
Procedure:
A. Drug Layering
1. Hydroxypropyl methylcellulose was dissolved in mixture of Isopropyl alcohol and
Dichloromethane.
2. Venlafaxine Hydrochloride was added to solution of step 1 under constant stirring.
3. Colloidal silicon dioxide and magnesium stearate were added to dispersion of step 2
under stirring.
4. Sugar spheres were then coated with a dispersion of step 3.
B. ER Coating of Drug Layered Beads
5. Solution of ethyl cellulose, polyvinyl pyrrolidone and triethyl citrate was prepared in
mixture of Isopropyl alcohol and dichloromethane.
6. Drug layered beads of step 4 were coated with solution of step 5.
7. Beads of step 6 were lubricated with Talc.
8. Lubricated beads were then filled in capsules of appropriate size.
In vitro dissolution study
In vitro release of extended release beads of venlafaxine as per composition of example 1 was done in 900 ml of various mediums in USP type II apparatus at a paddle speed of 50 rprn. The results are shown in table 1.
Table 1: Drug release profile of venlafaxine extended release beads of example 1.

(Table Remove)
EXAMPLE 2

PROCESS
A. Extrusion and Spheronization
1. Venlafaxine Hydrochloride and microcrystalline cellulose were blended together.
2. Solution of hydroxypropyl methylcellulose was prepared in IPA:Water combination.
3. Blend of step 1 was wetted using solution of step 2.
4. Wet mass of step 3 was extruded and the extrudes so obtained were then
spheronized.
5. The spheroids were dried in a fluidized bed drier.
B. Coating of Spheroids
1. Solution of Ethyl cellulose, povidone and triethyl citrate was prepared in mixture of
Isopropyl alcohol and dichloromethane.
2. Spheroids of step 5 were coated with solution of step 1.
3. Coated spheroids were then lubricated with talc.
4. Spheroids of step 8 were filled in capsules of appropriate size.
EXAMPLE 3

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PROCESS
C. Extrusion and Spheronization
1. Venlafaxine Hydrochloride and microcrystalline cellulose were blended together.
2. Solution of hydroxypropyl methylcellulose was prepared in water.
3. Blend of step 1 was wetted using solution of step 2.
4. Wet mass of step 3 was extruded and the extrudes so obtained were then
spheronized.
5. The spheroids were dried in a fluidized bed drier.
D. Coating of Spheroids
1. Solution of Ethyl cellulose, povidone and triethyl citrate was prepared in mixture of
Isopropyl alcohol and dichloromethane.
2. Spheroids of step 5 were coated with solution of step 1.
3. Coated spheroids were then lubricated with talc.
4. Spheroids of step 8 were filled in capsules of appropriate size.
The venlafaxine capsules were tested in various dissolution mediums such as pH 7.5 Phosphate buffer, distilled water, pH 6.8 Phosphate buffer, 0.1 N Hydrochloric acid and pH 4.5 acetate buffer according to the procedure described in the United States Pharmacopoeia XXIII, Apparatus USPII (Paddle) at 50 rpm.
TABLE 2: Dissolution profile of venlafaxine capsules (prepared by example 3) in various dissolution mediums at 37°C/50 rpm using apparatus USP II (Paddle)/ 900ml.

(Table Remove)
Further, bioequivalence study of the Venlafaxine hydrochloride 150 mg capsules of Example 3 was carried out on healthy male volunteers (n =13) taking Effexor XL® capsules (150 mg) produced by Wyeth as the reference.
Open randomized, 3 treatment, 3 period, 3 sequence, single dose crossover, was used for comparative bioavailability study of Venlafaxine hydrochloride 150 mg capsules of Example 3 against Effexor XL® capsules (150 mg) under fast and fed conditions.
T/R ratio under fed and fasting state for Cmax and AUC0-,x for Venlafaxine capsules of example 3 was within 80-125% as per FDA guidelines on bioequivalence. Results indicate that
Venlafaxine hydrochloride 150 mg capsules of Example 3 have bioavailability comparable to the reference product, Effexor XL® capsules (150 mg).
EXAMPLE 4
The composition and process for this example was same as that of example 3 except at step 1 and 2 of extrusion and spheronization wherein Venlafaxine Hydrochloride, hydroxypropyl methylcellulose and microcrystalline cellulose were blended together and granulated with purified water.
The capsule of the present invention thus provide an effective delivery system for the administration of Venlafaxine to patients in need of such treatment.

WE CLAIM:
1. An extended release pharmaceutical composition comprising plurality of beads
comprising:
i) extrudes or spheroids comprising venlafaxine or pharmaceutically acceptable salt
thereof, spheronizing aid and binder
ii) a coating comprising a mixture of ethyl cellulose and polyvinylpyrrolidone, wherein the extrudes or spheroids are prepared using an aqueous solvent.
2. The extended release pharmaceutical composition according to claim 1 wherein
aqueous solvent is water or mixture thereof with other organic solvents.
3. The extended release pharmaceutical composition according to claim 1 wherein ratio of
waterorganic solvents is at least 90:10.
4. The extended release pharmaceutical composition according to claim 1 wherein
aqueous solvent is water substantially free of organic solvents.
5. The extended release pharmaceutical composition according to claim 1 wherein
pharmaceutically acceptable salt thereof is venlafaxine hydrochloride.
6. The extended release pharmaceutical composition according to claim 1 wherein the
ratio of ethyl cellulose and polyvinylpyrrolidone ranges from 60:40 to 80:20.
7. The extended release pharmaceutical composition according to claim 1 wherein the
beads are further coated with non-functional coating.
8. The extended release pharmaceutical composition according to claim 1 wherein the
composition is tablet, pills, minitablets, capsule or sachet.
9. The extended release pharmaceutical composition according to claim 1 wherein the
plurality of beads are in the form of extrudes.
10. The extended release pharmaceutical composition according to claim 1 wherein the
plurality of beads are in the form of spheroids.
11. The extended release pharmaceutical composition according to claim 1 wherein
spheronization aid is selected from microcrystalline cellulose, cellulose powder, glyceryl

behenate, glyceryl monostearate, glyceryl palmitostearate and crosslinked polyvinyl pyrrolidone.
12. The extended release pharmaceutical composition according to any of the preceding
claims wherein pharmaceutical composition may further comprise of one or more
pharmaceutically inert excipients.
13. The extended release pharmaceutical composition according to claim 12 wherein
pharmaceutically inert excipient is selected from the group consisting of surfactants,
binder, diluents, disintegrants, lubricants, glidants, plasticizers, stabilizers and coloring
agents.
14. The extended release pharmaceutical composition according to claim 13 wherein binder
is selected from group consisting of polymethacrylates, ethylcellulose, povidone,
hydroxypropyl methylcellulose, and hydroxypropyl cellulose.
15. The process for preparation of pharmaceutical composition according to claim 1 wherein
process comprises the steps of:
i) preparing a solution or dispersion of binder in an aqueous solvent,
ii) granulating venlafaxine hydrochloride and spheronizing aid with a solution or
dispersion of binder,
iii) extruding and optionally spheronizing the mixture, drying and sieving, iv) preparing a solution or dispersion of mixture of ethyl cellulose and polyvinyl
pyrrolidone in suitable solvent v) coating the extrude or spheroid of step iii) with a polymeric solution or dispersion
obtained in step iii) and drying off the solvent
vi) optionally coating the beads obtained in step v) with a non functional coating, vii) compressing the beads into suitable size tablets or filling into capsules.
16. The process for preparation of pharmaceutical composition according to claim 15
wherein solution or dispersion of mixture of ethyl cellulose and polyvinyl pyrrolidone is
prepared in solvents selected from methylene chloride, isopropyl alcohol, acetone,
methanol, ethanol, water or mixture thereof.

17. The process for preparation of pharmaceutical composition according to claim 15
wherein coating is applied using techniques such as spray coating in a conventional
coating pan or fluidized bed processor or dip coating.
18. The process for preparation of pharmaceutical composition according to claim 15
wherein the pharmaceutical composition is tablet prepared by direct compression.
19. Use of the pharmaceutical composition as defined in any of the preceding claims for
treatment or prevention of depression, general anxiety disorder, social anxiety disorder
and post traumatic stress disorder.
20. An extended release pharmaceutical composition as herein described.