FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)

"EXTENDED RELEASE FORMULATION FOR VENLAFAXINE"

Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
B/2, Mahalaxmi Chambers 22, Bhulabhai Desai Road
Post Box No. 26511 Mumbai- 400 026, India

PROVISIONAL SPECIFICATION
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION BACKGROUND OF THE INVENTION
1. Technical Field
The invention relates to coated minitablets containing the active pharmaceutical ingredient venlafaxine in an extended release formulation and a process for the manufacturing of the said formulation. The formulation of the invention comprises of Venlafaxine HCl and other required pharmaceutically acceptable excipients
2. Description of the Related Art
Venlafaxine, a widely used antidepressant drug is freely soluble in water. It is currently available (Effexor XR; Wyeth) in a capsule dosage form containing extended release pellets prepared by extrusion-spheronization of the drug with microcrystalline cellulose and/or hydroxypropyl methylcellulose 2208 and coating the pellets prepared with ethylcellulose and hydroxypropyl methylcellulose 2910 in a fluidized bed coater. This technique requires special skills and expensive equipment. So there is a need for extended release tablet formulations of
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Venlafaxine while also retaining the advantage of easy dose-proportionality between the different strengths.
Attempts have been made to prepare extended release formulations of Venlafaxine by incorporating Venlafaxine HC1 in a matrix of hydrogel forming polymers either alone or in combination with hydrophobic polymers or wax-like substances. While all these attempts succeeded in matching the in-vitro drug release profile with the marketed formulation (Effexor XR; Wyeth), all but one (EP 1502587 Al) of these are unit-dose tablets wherein one complete dose is incorporated in a single tablet. The disadvantage with this strategy is that the release profile has to be individually matched with the reference product for all the strengths i.e. there is a lack of dose-proportionality between the different strength tablets which is necessary to obtain the biowaivers for the lower strengths. The other disadvantage is that it may be difficult to obtain the regulatory approval for such a generic formulation as it does not constitute a pharmaceutical equivalent to the reference product (Approved Drug Products with Therapeutic Equivalence Evaluations; 25th Edition; Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, U.S. Department of Health and Human Services) since the reference product is a capsule formulation.
SUMMARY OF THE INVENTION
One aspect of the present invention is to prepare a Venlafaxine extended release formulation
Yet another aspect of the present invention is to prepare a Venlafaxine extended release formulation which consists of multiple minitablets of the dosage form and resultant dosage form is a capsule containing the said minitablets.
In another embodiment of the present invention, the said formulation would provide the twin advantages of dose-proportionality and being a pharmaceutical equivalent of the reference listed drug.
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Accordingly, in another embodiment of the present invention, the core which essentially embodies an immediate release as illustrated by the drug release profile of Example 1 (Table 4) and the retarding effect on drug release is provided by the functional coating over the minitablets as illustrated by the drug release profiles of Examples 1.1, 1.2 and 1.3 (Table 4) provided herein unlike the prior art (EP 1502587 Al) wherein the core of the minitablets consists of a combination of a gelling agent, a non-swelling agent and a conjugation agent (that forms bonds between the gelling agent and the non-swelling agent or between the drug substance and the gelling or the non-swelling agent, causing the swelling property of the core to be limited). The core of the minitablets in this application (EP 1502587 Al) is a functional core which plays the major part in retarding the drug release as illustrated by the examples given in the description of the invention. It further provides for a coating layer (formed by compression coating) or a coating film over the minitablets to limit the initial rapid drug release.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention provides an effective process for the manufacturing of the formulation. The formulation of the present invention is in the form of coated extended release minitablets
filled into a capsule.
The invention relates to formulations i.e. coated minitablets containing the active pharmaceutical ingredient venlafaxine and a process for the manufacturing of the said formulation. The formulation of the invention comprises of Venlafaxine HCl API and other required pharmaceutical^ acceptable excipients.
The formulations of the present invention use Venlafaxine HCl and other required
pharmaceutical acceptable excipients selected from amongst the diluents, hydrophobic polymers, glidants and lubricants. The hydrophobic polymers are water-insoluble and are
selected from the group comprising of ethylcellulose, ammonio methacrylate copolymers types A and B as described in USP, methacrylic acid copolymer types A, B and C as described in USP, polyacrylate dispersion 30% as described in Ph.Eur., polyvinyl acetate dispersion, cellulose acetate, cellulose propionate (low, medium or high 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), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) and poly(octadecyl acrylate). It is preferably ethylcellulose.
The formulation of the present invention is in the form of coated extended release minitablets filled into a capsule. The coating composition may comprise of agents selected from the group consisting of hydrophobic polymers, channel forming agents, plasticizers, anti-tacking agents, fillers, coloring agents and opacifiers. The hydrophobic polymers are water-insoluble and are selected from the group comprising of ethylcellulose, ammonio methacrylate copolymers types A and B as described in USP, methacrylic acid copolymer types A, B and C as
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described in USP, polyacrylate dispersion 30% as described in Ph.Eur., polyvinyl acetate dispersion, cellulose acetate, cellulose propionate (low, medium or high 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), poly(hexyl methacrylate), poly(isodecyl methacrylate),
poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) and poly(octadecyl acrylate). It is preferably ethylcellulose. The channel-forming agent is water soluble and may be selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, sucrose, mannitol, lactose or any other substance capable of playing the same role as obvious to those skilled in the art. It is preferably hydroxypropyl methylcellulose.
The process for the manufacturing involves the blending of Venlafaxine HCl with the diluent / filler and hydrophobic polymer followed by granulation in a high shear mixer using an organic solvent in which both the drug substance and the hydrophobic polymer are soluble in order to form bridges between the drug substance and the hydrophobic polymer. The granules are dried and reduced to the desired size and then lubricated with the lubricant(s). Alternatively, the granulation equipment used can be a fluidized bed granulator in which Venlafaxine HCl, hydrophobic polymer and the diluent are granulated by spraying the organic solvent. The lubricated blend is compressed into minitablets and the tablets are coated with an insoluble coating composition.
Alternatively, the granulation can be an aqueous process in which Venlafaxine HCl and the diluent are granulated with an aqueous dispersion of ethylcellulose (e.g. Surelease® or Aquacoat®) or ammonio methacrylate copolymer (Eudragit RS 30D® or Eudragit RL 30D®)
The minitablets coating composition can be aqueous consisting of an aqueous dispersion of ethylcellulose (e.g. Surelease® or Aquacoat®) or ammonio methacrylate copolymer (Eudragit RS 30D® or Eudragit RL 30D®) in combination with a channel-forming agent selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl
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cellulose, sucrose, mannitol, lactose or any other substance capable of playing the same role as obvious to those skilled in the art. The preferable coating composition consists of ethylcellulose aqueous dispersion and polyvinyl pyrrolidone as channel forming agent.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims. The percent w/w formula composition of the example of the present invention is tabulated in Table 1.
The capsules were studied for the dissolution studies in 900 ml of Water at 37°C using USP Dissolution Apparatus Type I at an agitation of 100 RPM. The dissolution of venlafaxine from the Effexor XR Capsules 150 mg (Mfd. By Wyeth) was studied under the same conditions for comparison. The data obtained from the dissolution studies are tabulated in Table 4. The dissolved venlafaxine is expressed in cumulative percent of drug dissolved over an elapsed time period in hours.
Table 1

Sr.No. Ingredients % w/w of core
Example 1
1. Venlafaxine Hydrochloride 53.88
2. Ethylcellulose 100 cP(Ethocel 100 cP Std. Prem. FP ®) 20.32
3. Microcrystalline Cellulose (AvicelPHlOl®) 13.80
4. Magnesium Stearate 0.89
5. Absolute Ethanol q.s.
Venlafaxine Hydrochloride, Ethylcellulose 100 cP (Ethocel 100 cP Std. Prem. FP Ò) and Microcrystalline Cellulose (Avicel PH 101 ®) were blended in a high shear mixer and granulated using Absolute Ethanol. The wet mass was dried, screened through No. 30 mesh sieve, lubricated with magnesium stearate in a double cone blender. The lubricated blend was
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compressed into minitablets of 3 mm diameter and the minitablets were then given functional coating of the composition as given in Table 2.
Table 2

Sr. No. Ingredients % w/w of coating composition
1. Ethylcellulose 22 cP(Ethyl Cellulose N-22 Pharm. ®) 2.57
2. Hydroxypropyl Methylcellulose 6 cP (Methocel E6 LV ®) 1.10
3. Isopropyl Alcohol 35.99
4. Methylene Chloride 60.34
The coating composition of Table 2 was provided over the minitablets of the composition of Table 1. Two batches were prepared with different coating levels - 10.4% w/w for Example 1.1 and 12.5% for Example 1.2 whose dissolution profiles are given in Table 4.
Another batch was prepared using an aqueous coating composition as given in Table 3, giving a coating of 12.5% w/w whose dissolution profile is given in Table 4 (Example 1.3).
Table 3

Sr. No. Ingredients % w/w of coating composition
1. Ethylcellulose Aqueous Dispersion (Surelease ®) 36.00
2. Polyvinyl Pyrrolidone (Plasdone K-30 ®) 1.00
3. Purified Water 63.00
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Uncoated minitablets of the composition as given in Table 1 were also subjected to dissolution study. The dissolution result (Example 1, Table 4) is exemplary of an immediate release profile.
Table 4

Tablet Samples 1 hr 2 hr 4 hr 6 hr 8 hr 10 hr 12 hr 16 hr 24 hr
Example 1 99
Example 1.1 5 13 32 50 61 72 81 92 97
Example 1.2 31 62 94 100 99 101 100 99 100
Example 1.3 0 3 16 32 48 57 65 75 83
EffexorXRÒ150 mg Capsules 7 17 39 59 69 79 86 89 91
Thus it is evident that the present invention provides a means to control the dissolution rate of venlafaxine by varying the coating level.
The detailed step wise procedure for the manufacturing process is as follows.
1. Venlafaxine Hydrochloride is blended with Ethocel 100 cP Std. Prem. FP and Avicel PH
101 in high shear mixer.
2. The blended mass is granulated in the mixer using absolute ethanol.
3. The granules are dried.
4. The dried granules are reduced to the desired size in oscillating granulator using No. 30 mesh sieve.
5. The blended granules are lubricated with Magnesium Stearate.
6. The lubricated granules are compressed into minitablets of 3 mm diameter.
7. The compressed tablets are coated using a solution of Ethyl Cellulose N-22 Pharm. and Methocel E6 LV.
8. The coated minitablets are filled into capsules of different strengths by varying the number of tablets per capsule.
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It is clear that the desired dissolution of the venlafaxine extended release capsules could be achieved with the composition of the present invention which provides a simple means of achieving dose-proportionality between different strengths.
The probable ranges of the individual components of the formula composition are mentioned in Table 5.
Table 5

Sr. No. Ingredients % w/w of dosage form
1. Venlafaxine Hydrochloride 40.0% to 90.0 %
2. Ethylcellulose 100 cP (Ethocel 100 cP Std. Prem. FP) 5.0 % to 50.0 %
3. Microcrystalline Cellulose (Avicel PH lOl) 10.0% to 50.0%
4. Magnesium Stearate 0.10% to 5.0%
5. Ethylcellulose 22 cP(Ethyl Cellulose N-22 Pharm.) 5.0 % to 20.0 %
6. Hydroxypropyl Methylcellulose 6 cP (Methocel E6 LV) 0.90% to 10.0%
7. Water q.s.
8. Isopropyl Alcohol q.s.
9. Methylene Chloride q.s.
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Dated this twenty second (22nd) day of June, 2005

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ABSTRACT
An extended release pharmaceutical composition in solid dosage form is provided comprising a core comprising a therapeutically effective amount of venlafaxine or a pharmaceutically acceptable salt thereof and an extended release coating associated with the core, wherein the core provides an immediate release of venlafaxine or a pharmaceutically acceptable salt thereof and the extended release coating provides an extended release of venlafaxine or a pharmaceutically acceptable salts thereof.
Dated this twentieth (20th) day of June, 2006

2 0JUN 2006
I