FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "Extended Release Formulation of Venlafaxine Hydrochloride"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification describes the invention.

FIELD OF THE INVENTION
The invention relates to an oral extended release solid pharmaceutical composition comprised of a therapeutically effective amount of venlafaxine hydrochloride, about 10 to 70% of low-substituted hydroxypropyl cellulose, microcrystalline cellulose or a mixture thereof and at least one more pharmaceutically acceptable excipient in the form of spheroids. These spheroids are coated with a mixture of pH independent hydrophobic and hydrophilic polymeric release retardant. The invention further relates to process for preparation of venlafaxine hydrochloride extended release formulation which is suitable for scale up and commercial level manufacturing.
BACKGROUND OF THE INVENTION
Venlafaxine, l-[(2-dimethylarnino)-l-(4-methoxyphenyl) ethyl] cyclohexanol, is an important drug for the treatment of depression. Venlafaxine hydrochloride is presently administered to adults as immediate or extended release tablet or capsule dosage form (Effexor and Effexor XR) in doses ranging from 37.5 to 150 mg/day. In case of immediate release formulations rapid dissolution results in a rapid increase in blood plasma levels of the active compound shortly after administration followed by a decrease in blood plasma levels over several hours as the active compound is eliminated or metabolized, until subtherapeutic plasma levels are approached after about twelve hours following administration, thus requiring additional dosing with the drug. With the plural daily dosing regimen, the most common side effect is

nausea, experienced by about forty five percent of patients under treatment with venlafaxine hydrochloride. Vomiting also occurs in about seventeen percent of the patients. This is taken care of by formulation of extended release formulation. The modified release profile as achieved using extended release formulation results in constant drug levels and minimizes the side effects arising due to fluctuations in drug plasma levels due to plural dosing regimen. This leads to increased patient compliance and convenience because of once a day administration of therapeutically effective amount of venlafaxine hydrochloride.
Even though it is desirable to have extended or controlled release formulation of venlafaxine hydrochloride, it is a challenge to design extended release dosage form with desirable dissolution profile. This is because venlafaxine hydrochloride is highly crystalline, highly soluble and high dose molecule.
There are numerous attempts in prior art directed towards provisions of modified release dosage forms for venlafaxine.
U. S. Patent No. 6,703,044 relates to venlafaxine solid delayed burst release formulation made up of a burst controlling agent such as microcrystalline cellulose and a disintegrant coated with water insoluble neutral methacrylate copolymer and chanellising agent. The rate of drug release from such formulations is not predictable as it depends upon ingress of gastric fluid through channels and breaking of the film coat, following which the burst release of drug occurs from the drug core.

U. S. Patent Application US20060182797 provides a sustained release venlafaxine capsule formulation containing mini tablets designed as drug cores partially coated with functional coating. The mini tablet cores are made up of combination of well known gelling and non gelling excipients and coated with conventional water soluble polymer.
Thus conventional excipients are employed to achieve the modified release of venlafaxine from formulations like tablets or minitablets. In spite of this the desired zero order release kinetics is not always achieved and special efforts are to be put to design the extended dosage form of water-soluble dug substances such as venlafaxine hydrochloride.
Numerous attempts to produce extended release tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies.
Design of multiparticulate controlled release system was then evaluated using extrusion spheronization technique. U. S. Patent No. 6,274,171 describes an extended release formulation of venlafaxine hydrochloride comprising spheroids prepared using 50 to 94% microcrystalline cellulose (MCC) and hydroxypropyl methylcellulose (HPMC) coated with a mixture of ethyl cellulose and hydroxypropyl methylcellulose. According to the inventor, addition of hydroxypropyl methylcellulose to venlafaxine hydrochloride-microcrystalline cellulose mix made

production of spheroids practical. However, use of such high concentration of microcrystalline cellulose along with hydroxypropyl methylcellulose may impart stickiness to the extruded mass of soluble drug such as venlafaxine hydrochloride, thus resulting in twinning and agglomeration of pellets making the process cost and time intensive. Further spheroids with more than 50% microcrystalline cellulose may tend to get uneven surface, making the coating process very difficult. Such spheroids tend to exhibit undesirable and incomplete release profile as a result of uneven functional coating on spheroids surface.
Thus there is a need for alternative or modified formulation employing combination of excipients which would confer desired characteristics such as sphericity and smoothness to the spheroids of highly water soluble and high dose actives such as venlafaxine hydrochloride and will reduce the processing time for formulation and coating.
After rigorous experimentation it has been found by inventors that venlafaxine extended release formulation comprised of spheroids having about 10% to 70% of low-substituted hydroxypropyl cellulose, microcrystalline cellulose or a mixture thereof and at least one more pharmaceutically acceptable excipient result in formation of spheroids with characteristic features such as sphericity and smoothness which yield desirable dissolution profile after coating with polymeric release retardants. The process is simple, cost effective and results into dissolution profile which is comparable to innovator's formulation. Use of water insoluble low-

substituted cellulosic excipient along with less than 50% microcrystalline cellulose confers greater productivity in terms of extrusion speed and yield. Such combination of excipients also results in excellent molding property and wet mass of active can be transformed into pellets having physical stability and integrity. SUMMARY OF THE INVENTION
The invention relates to an oral extended release solid pharmaceutical composition in the form of spheroids comprising a therapeutically effective amount of venlafaxine hydrochloride, about 10% to 70% of low-substituted hydroxypropyl cellulose, microcrystalline cellulose or a mixture thereof and at least one more pharmaceutically acceptable excipient, wherein the spheroids are coated with a mixture of hydrophobic and hydrophilic polymeric release retardant. The invention further relates to process for preparation of Venlafaxine hydrochloride extended release formulation which is suitable for scale up and commercial level manufacturing.
DETAILED DESCRIPTION
The present inventors have addressed the need of developing an extended release dosage form of highly water soluble and high dose active active such as venlafaxine in the form of spheroids comprised of a mixture of low-substituted hydroxypropyl cellulose and microcrystalline cellulose, along with at least one more pharmaceutically acceptable excipient. The amount of microcrystalline cellulose used is less than 50% by weight spheroids. The spheroids are coated using

combination of pH independent hydrophilic and hydrophobic polymeric release
retardant. Venlafaxine coated spheroids exhibit desired drug release profile over
extended time period and the process is suitable for scale up and commercial level
manufacturing.
A "therapeutically effective amount" means the amount of a compound that, when
administered to a mammal for treating a state, disorder or condition is sufficient to
effect a treatment. The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, physical condition and
responsiveness of the mammal to be treated.
The term "release retardant" as used here means a pharmaceutically acceptable
excipient that can retard or slow down the release of an active pharmaceutical
ingredient from the formulation.
The term "hydrophilic polymer" as used here includes a pharmaceutically acceptable
polymeric excipient that has affinity for water, and becomes soluble or swells after it
gets into contact with physiological fluid or aqueous medium.
The hydrophilic polymer is selected from the group comprising of cellulose
derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose,
hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethylpropyl cellulose,
carboxymethyl cellulose, sodium carboxymethyl cellulose; polymers of acrylic acids
such as carbopol derivatives; natural polymers like pectin, guar gum, inulin, xanthan

gum, locust bean gum, sodium alginate; other hydrophilic polymers such as polyethylene glycol, polyethylene oxide, and the like; or the combination thereof. The term "hydrophobic polymer" as used here includes a pharmaceutically acceptable polymeric excipient that is insoluble in water or in an aqueous buffer solution at a pH anywhere in the range of 1.0 to 8.0. Such polymer does not even swells after it gets into contact with physiological fluid or aqueous medium. Exemplary hydrophobic polymers include cellulose ethers (cellulose alkyl ethers, including cellulose C1-6 alkyl ethers, such as methylcellulose, ethylcellulose, propylcellulose, ethylmethylcellulose, ethylpropylcellulose, isopropylcellulose, butylcellulose and the like; cellulose aralkyl ethers such as benzyl cellulose and the like; cellulose cyanoalkyl ethers such as cyanoethyl cellulose, cyanomethyl cellulose, cyanoethylmethyl cellulose, cyanopropyl cellulose, and the like), cellulose esters (cellulose organic acid esters such as cellulose acetate butyrate, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate propionate and the like), methacrylic acid-acrylic acid copolymers (e.g., EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, Rohm GmbH, Germany) and the like. Of these polymers, cellulose C1-6 alkyl ethers, aminoalkyl methacrylate copolymers (e.g., EUDRAGIT® RL, EUDRAGIT® RS, Rohm GmbH, Germany) and ethyl acrylate-methyl methacrylate copolymers (e.g., EUDRAGIT® NE, Rohm GmbH, Germany) are preferred. In one embodiment, ethylcellulose (ETHOCEL®, Dow Chemical) is preferred.

"Reduced initial burst release" as per this invention means the reduction in release of active ingredient from the dosage form at initial time points.
Venlafaxine spheroid formulations were prepared using low-substituted hydroxypropyl methyl cellulose (L-HPC) alone or in combination with other diluents such as microcrystalline cellulose and corn starch. Different ratios of venlafaxine hydrochloride and L-HPC as well as microcrystalline cellulose and corn starch were tried. Microcrystalline cellulose was used in amounts less than 50% by weight of the spheroids.
During the trials it was found that L-HPC is a preferred excipient in this formulation over microcrystalline cellulose and was selected for extrusion spheronization. L-HPC is insoluble in water and has swelling action in water. It was found that the formulation with L-HPC resulted in spheroids which are superior than those made from microcrystalline cellulose alone. Because L-HPC is non-ionic, it is less reactive to active ingredients compared with ionic excipients. Its smaller particles can easily pass through the screen. It provides wet mass with a "buffer effect" in which the wet mass accepts a wider range of water content. L-HPC plasticizes wet mass and shows greater productivity (extrusion speed and yield).The final pellets show quick disintegration and better friability compared with non-L-HPC formulation. In one of the embodiments, the drug was mixed with L-HPC along with other excipient and wet granulated using suitable granulation solvent. The wet mass was

passed through extrusion spheronizer and the resulting spheroids were dried. In the
extrusion process, heat buildup occurred which dried out the extrudate, but use of
mixture of L-HPC with microcrystalline cellulose or L-HPC alone made production
of spheroids practical, resulting into spheroids with smooth surface area, suitable for
further coating process.
The resulting spheroids can be coated and resifted to remove any agglomerates
produced in the coating steps. During the coating process samples of the coated
spheroids may be tested for their distribution profile. If the dissolution occurs too
rapidly, additional coating may be applied until the spheroids present a desired
dissolution rate.
Extended release of the active agent from the formulation of present invention is
achieved by use of at least one pH independent polymer.
In one of the embodiment of this invention, the composition employs a mixture of
pH independent polymeric release retardants.
In still one more embodiment of the present invention, the composition makes use of
combination of hydrophilic and hydrophobic polymer such as hydroxypropyl methyl
cellulose and ethyl cellulose or the like.
pH independent polymeric release retardants are dissolved in the non aqueous
solvents such as dichloromethane and isopropyl alcohol to get a coating system.
This coating solution is applied to the venlafaxine spheroids by using the standard
coating equipment.

Compositions of the present invention generally contain at least one
pharmaceutically acceptable carrier conventionally used in the art of tablet and/or
capsule formulation.
Pharmaceutical excipients are routinely incorporated into solid dosage forms to ease
the manufacturing process as well as to improve the performance of the dosage form.
These can include diluents, lubricants, granulating aids, anti-adherents, gildants and
the like; or combinations thereof.
The present invention may include one or more fillers or excipients in an amount within the range of from about 0 to about 50% by weight and preferably from about
1 to about 40% by weight such as lactose, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose. The binders are selected from the group, comprising of starch, polyethylene glycol, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polymethacrylic acid derivatives, ethyl cellulose, cross-linked carboxymethylcellulose, low viscosity hydroxypropyl methyl cellulose and hydroxypropylcellulose and natural and synthetic gums. Binders may be incorporated into the system at a concentration of about 0.5-20% by weight, preferably 1-10% and more preferably 2-7.5% by weight. The formulation may include one or more lubricants in an amount within the range of from about 0.2 to about 8% and preferably from about 0.5 to about 2% by weight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium

stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate,
carnauba wax and the like and mixtures thereof. Other conventional pharmaceutical
ingredients, which may optionally be present, include preservatives, stabilizers, FD
& C colors and the like; or combinations thereof.
The invention relates to an oral extended release solid pharmaceutical composition of
venlafaxine comprising low-substituted hydroxypropyl cellulose and
microcrystalline cellulose along with at least one pharmaceutically acceptable
excipient. The invention further relates to process for preparation of venlafaxine
extended release capsule formulation in the form of spheroids which is suitable for
scale up and commercial level manufacturing.
The drug release study from such formulation is carried out using USP dissolution
apparatus I in water using 900 ml volume of dissolution media at 100 rpm.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and
are intended to be included within the scope of the present invention.

WORKING EXAMPLES
Example I: Venlafaxine extended release spheroid formulation

Sr. No. Ingredients Mg/capsule
1. Venlafaxine HCl 169.7
2. Low substituted hydroxypropyl cellulose (LHPC LH 31) 135
3. Microcrystalline cellulose (Avicel PH101) 90.55
4. Hydroxypropylmethyl cellulose (Methocel 2208) 3 cps 2.25
5. Starch B 30
6. Ethyl cellulose 10FP 22.5
7. Purified water QS
Weight of uncoated spheroids 450
Process for preparation:
1) Sift Venlafaxine HCI, Low-substituted hydroxypropyl cellulose, macrocrystalline cellulose, starch, hydroxypropylmethylcellulose and ethylcellulose through 40 mesh sieve.
2) Mix the step 1 mixture in rapid mixer granulator.
3) Granulate step 2 in rapid mixer granulator by using purified water.
4) Pass the dough mass through extruder and spheronize it.
5) Dry the spheroids at 50°C-55°C in tray dryer.

Example II: Venlafaxine extended release spheroid formulation

Sr. No. Ingredients Mg/capsule
1. Venlafaxine HC1 169.7
2. Low substituted hydroxypropyl cellulose (LHPC LH 31) 90
3. Microcrystalline cellulose (Avicel PH 101) 167.8
4. Starch B 22.5
5. Purified water QS
Weight of uncoated spheroids 450
Process for preparation:
1) Sift Venlafaxine HC1, microcrystalline cellulose, starch and Low-substituted hydroxypropyl cellulose through ASTM # 40 mesh.
2) Mix step 1 mixture in rapid mixer granulator.
3) Granulate step 2 in rapid mixer granulator by using water.
4) Pass the dough mass through extruder and spheronize it.
5) Dry the spheroids at 50°C-55°C in tray dryer.

Example III: Venlafaxine extended release spheroid formulation

Sr. No. Ingredients Mg/capsule
1. Venlafaxine HC1 169.7
2. Microcrystalline cellulose (Avicel PH 101) 158.8
3. Starch B 22.5
4. Low substituted hydroxypropyl cellulose (LHPC LH 31) 90
5. Colloidal silicon dioxide 9
6. Purified water* QS
Weight of uncoated spheroids 450
* Removed during processing not considered in final weight of product. Process for preparation:
1) Sift Venlafaxine HC1, microcrystalline cellulose, starch, low-substituted hydroxypropyl cellulose and colloidal silicon dioxide through ASTM # 40 mesh.
2) Mix stepl mixture in rapid mixer granulator.
3) Granulate step 2 in rapid mixer granulator by using water.
4) Pass the dough mass through extruder and spheronize it.
5) Dry the spheroids at 50°C-55°C in tray dryer.
The spheroids prepared in this way possess smooth surface area which can be coated with functional polymers.

Preparation of extended release Venlafaxine Capsule formulation:
Spheroids prepared in example I, II and III are coated with a release controlling coating composition comprised of ethylcellulose and hydroxypropylmethylcellulose. Release controlling Coating of Spheroids:

Sr. No. Ingredients Mg/capsule
1. Ethylcellulose (Aqualon N50) 30.6
2. Hydroxypropylmethyl cellulose (Methocel E5) 5.4
3. Dichloromethane* 410
4. Isopropyl alcohol* 274
Weight buildup 36
Weight of Coated Spheroids 486
Lubrication before filling in capsule shell
5. Purified talc 2
6. Magnesium stearate 2
Fill weight of capsule 490
Coating of venlafaxine spheroids: (For Example I, II and III)
1) Coat dried spheroids with release controlling coating solution which is based on Non aqueous solvent by using Fluidized Bed Processor and dry it.
2) Mix the coated spheroids with talc and magnesium stearate in low shear blender for 3 minutes at slow speed.
3) Fill the lubricated spheroids in Hard gelatin capsule shell by using suitable capsule filling machine.

Drug Release Profile of Venlafaxine hydrochloride extended release capsules:
Dissolution Medium: Water
Apparatus: USP Type I (Basket)
Speed: 100 rpm
Volume: 900 ml
Time Points: 2, 4,8,12 and 20 hours

Comparative Dissolution Profile
Time Points (Hr) Effexor XR Capsules 150 mg Example III
2 13 5
4 37 31
8 63 67
12 75 83
20 85 93
The drug release profile of Example III Venlafaxine hydrochloride capsule formulation was comparable with Innovator's formulation Effexor XR as seen from the data provided in the table.

Example IV
Venlafaxine hydrochloride ER Capsule

Sr.No. Ingredients Qty/Capsule
Preparation of Spheroids
Venlafaxine hydrochloride 169.7
Low-substituted hydroxypropyl cellulose 257.8
Corn starch (Maize Starch B) 22.5
Purified Water qs
Weight of Spheroids 450
Release controlling Polymer Coating
Ethylcellulose (N-50) 30.6
Hydroxypropyl methyl cellulose 5.4
Talc 3.5
Methylene chloride* 533
Lubrication
Magnesium stearate 2.5
Fill Weight of Capsule 492
* Removed during manufacturing processing not considered in final weight of product

Process of preparation for spheroids
1) Sift venlafaxine hydrochloride, low-substituted hydroxypropyl cellulose and starch, colloidal silicon dioxide through ASTM # 40 mesh.
2) Mix step 1 mixture in rapid mixer granulator.
3) Granulate step 2 in rapid mixer granulator by using water.
4) Pass the dough mass through extruder and spheronize it.
5) Dry the spheroids at 50°C-55°C in tray dryer.
The spheroids prepared in this way possess smooth surface area which can be coated with functional polymers. Coating of venlafaxine spheroids
1) Coat dried spheroids with release controlling coating solution which is based on Non aqueous solvent by using Fluidized Bed Processor and dry it.
2) Mix the coated spheroids with talc and magnesium stearate in low shear blender for 3 minutes at slow speed.
3) Fill the lubricated spheroids in hard gelatin capsule shell by using suitable capsule filling machine.
The final pellets produced from L-HPC exhibit superior surface property such as sphericity and better yield.

We claim,
1. An oral extended release capsule formulation comprising,
a. a therapeutically effective amount of venlafaxine hydrochloride
b. about 10% to 70% of low-substituted hydroxypropyl cellulose,
microcrystalline cellulose or a mixture thereof
c. at least one more pharmaceutical^ acceptable excipient;
in the form of spheroids wherein the spheroids are coated with a film coating composition comprised of a mixture of pH independent polymeric release retardants.
2. An extended release venlafaxine formulation of claim 1, wherein microcrystalline cellulose is used in amounts from about 5 to 40% by weight of the spheroids.
3. An extended release venlafaxine formulation of claim 1, wherein at least one more pharmaceutically acceptable excipient is selected from the group of diluent, binder, filler, glidant, lubricant, film forming agent, plasticizer and the like.
4. An extended release venlafaxine formulation of claim 1, wherein the spheroids are coated with a mixture of pH independent polymeric release retardants selected from hydrophilic polymer and hydrophobic polymer.

5, An extended release venlafaxine formulation of claim 4, wherein pH
independent hydrophilic polymeric release retardant is hydroxypropyl methyl
cellulose.
6. An extended release venlafaxine formulation of claim 4, wherein pH independent hydrophobic polymeric release retardant is ethyl cellulose.
7. A process for preparing extended release venlafaxine formulation, comprising
a. mixing venlafaxine hydrochloride with about 10% to 70% of low-
substituted hydroxypropyl cellulose, microcrystalline cellulose or a mixture
thereof and at least one more pharmaceutically acceptable excipient to get the
powder blend,
b. adding granulation solvent in above blend to get wet mass.
c. passing the wet mass through extruder spheronizer to get the spheroids.
d. drying the spheroids at 50°C-55°C in tray dryer.
e. coating the dried spheroids using mixture of pH independent hydrophilic
and hydrophobic polymeric release retardant.
f. lubricating the coated spheroids and filling into the capsule.
8, A process for preparing extended release venlafaxine formulation as claimed
in claim 7, comprising

a. mixing venlafaxine hydrochloride with about 10% to 70% of low-
substituted hydroxypropyl cellulose, microcrystalline cellulose or a mixture
thereof along with other excipients.
b. adding water in above blend to get wet mass.
c. passing the wet mass through extruder spheronizer to get the spheroids.
d. drying the spheroids at 50°C-55°C in tray dryer.
e. coating the dried spheroids using mixture of hydroxypropyl methyl
cellulose and ethyl cellulose.
f. lubricating the coated spheroids and filling into the capsule.
9. An oral extended release venlafaxine formulation as described in the example.