FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
C complete specification
[See section 10 and rule 13]
TITLE
"SUSTAINED RELEASE FORMULATION FOR VENLAFAXINE"
Applicant: TORRENT PHARMACEUTICALS LIMITED, Torrent House, Off Ashram Road, Near Dinesh hall, Ahmedabad - 380 009, Gujarat, India.
The following specification describes the invention.

SUSTAINED RELEASE FORMULATION OF VENLAFAXINE
FIELD OF THE INVENTION
The present invention relates to sustained release pharmaceutical formulation of Venlafaxine for once daily administration.
The present invention also provides a process for preparing said formulation.
BACKGROUND OF THE INVENTION
Venlafaxine, chemically named (±) l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl]-cyclohexanol, is an antidepressant disclosed in EP-A-0 112 669. Presently Venlafaxine hydrochloride is administered to adults as conventional immediate release tablets or as 24-hour extended-release multiparticulate capsules.
Venlafaxine hydrochloride is highly soluble in water. It is known that it is very difficult to develop a pharmaceutical form with a very slow dissolution rate of freely soluble drug. Besides that, Venlafaxine hydrochloride is polymorphic, so dissolution is dependent also on polymorphic form and particle size of particular polymorphic form. Therefore, it is a special task to develop such a pharmaceutical formulation that would sustain and control the dissolution of freely soluble drug over 24 hour period. As concerns more particularly venlafaxine hydrochloride, used particularly in the treatment of depression, the immediate release tablet has dosing frequency of two to three times a day and has significant disadvantage of nausea and vomiting.
It is known that it is useful for certain active principles to undergo controlled release so as to limit the number of doses whilst ensuring optimum effectiveness. Thus, the administration of oral forms with immediate release requires several administrations per day, which in addition to the inconvenience that arises can disturb the observance of the treatment. Hence
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the controlled release formulation for venlafaxine hydrochloride is all the more necessary.
PRIOR ART
US 6274171 and WO 99/22724 disclose encapsulated venlafaxine extended release dosage formulation of venlafaxine hydrochloride, which provides in a single dose, a therapeutic blood serum level over a twenty four hour period. Gelatine capsules are filled with film coated spheroids containing venlafaxine hydrochloride. These patents disclose manufacturing of venlafaxine hydrochloride pellets using extrusion spheronisation which are then further coated with ethylcellulose and hydroxypropylmethylcellulose using organic solvent.
WO2003041692 discloses an extended release composition comprising as active compound Venlafaxine Hydrochloride, in which Venlafaxine Hydrochloride is coated on a non pareil inert core, which coated core is then coated with polymeric layer which enables the controlled release of the Venlafaxine Hydrochloride.
PCT application WO 02/102129 A2 disclose information about sustained release formulations of Venlafaxine hydrochloride. These formulations are based on pellets, beads or spheres. The pellets or core is prepared by either extrusion spheronization or layering techniques and a polymer layer is provided over the core for the sustained release of Venlafaxine hydrochloride.
WO2004091580 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.
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The above-mentioned prior arts (US 6274171, WO 99/22724, WO2003041692 and WO2004091580) use polymers to achieve extended release of venlafaxine hydrochloride.
The use of polymers to achieve extended release has various disadvantages, such as
1. It requires formulation development of polymeric dispersion or solution.
2. The film formation property of the respective polymer depends upon the formulation of polymeric dispersion or solution
3. During the manufacturing process it is required to maintain product bed temperature above glass transition temperature of the said polymeric solution or dispersion.
4. Lot to lot variation in formulation of polymeric dispersion or solution may change the film formation property with respect to glass transition temperature. Hence the manufacturing process becomes critical.
Thus, there is a need in the industry to develop the venlafaxine hydrochloride extended release formulation without involving polymers.
The present invention relates to a formulation of a sustained release pellets containing Venlafaxine, which does not involve use of polymers
OBJECT OF THE INVENTION
The object of the present invention is to provide a sustained release pharmaceutical formulation of Venlafaxine for once daily administration.
Another object of the present invention is to provide a process for preparing said formulation.
SUMMARY OF THE INVENTION
The instant invention relates to a sustained release pharmaceutical formulation of Venlafaxine for once daily administration, which gives predictable drug release over an extended period of time.
Instant invention employs use of triglycerides as a release controlling agent.
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Instant invention also discloses simple and cost effective process of manufacturing sustained release dosage form of Venlafaxine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a sustained release pharmaceutical formulation of Venlafaxine for once daily administration, which gives predictable drug release over an extended period of time.
Further, present invention also relates to a method for producing a sustained release dosage form of Venlafaxine.
In one general aspect there is provided a sustained release formulation of venlafaxine, which is made up of a venlafaxine core subsequently coated by rate controlling agents.
In one preferred embodiment, Venlafaxine is mixed with pharmaceutically acceptable excipients and resultant mixture is extruded and spheronised in to pellets. The pellets are then coated with triglyceride to achieve sustained release.
In another embodiment, Venlafaxine is mixed with pharmaceutically acceptable excipients and resultant mixture is extruded and spheronised in to pellets. The pellets are then coated with triglyceride and binder to achieve sustained release.
In yet another embodiment, inert core is coated with venlafaxine, which is further coated with triglyceride to achieve sustained release.
The term "Sustained release" as used herein refers to the release of an active ingredient such as a drug from a composition, formulation or dosage form in
which the active ingredient is released according to a desired profile over an
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extended period of time and is taken to encompass controlled release, modified release, prolonged release, pulsatile release, delayed release and the like.
Such release rates can provide therapeutically effective levels of active ingredient for an extended period of time and thereby provide a longer period of pharmacologic or diagnostic response as compared to conventional rapid release dosage forms. Such longer periods of response offers many
inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.
A sustained release formulation is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bio-availability, convenience, and patient compliance, as well as minimizing side effects associated with inappropriate immediate release rates such as a high initial release rate and, if undesired, uneven blood or tissue levels.
The term "dosage form" denotes any form of the formulation that contains an amount sufficient to achieve a therapeutic effect with a single administration.
The term "Venlafaxine" as used herein includes Venlafaxine or its pharmaceutically acceptable salt, solvate, polymorph, enantiomer or mixtures thereof,
The dosage form of the present invention may include the venlafaxine in a range of about 1 mg to about 300 mg. More preferably dosage forms may contain either 37.5 mg, 75 mg or 150 mg of venlafaxine.
The sustained release oral dosage form of the present invention may be administered once daily.
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The sustained release dosage form as per the instant invention comprises Venlafaxine, at least one release controlling triglyceride and other pharmaceutically acceptable excipient(s). These pharmaceutical ly acceptable excipients are selected from the following categories but not limited to diluents, fillers, binders, glidants, lubricants, and/or plasticizers.
The term "release controlling triglyceride" as used herein refers to any suitable triglyceride, capable of retarding the release of active ingredient
present in the dosage form as per the present invention. "Suitable release controlling triglyceride" is intended to mean mixture of triglycerides of fatty acids, which can control the release of drug from the dosage form. Such compounds include, by way of example and without limitation, hydrogenated castor oil, hydrogenated vegetable oil, hard fat and other materials known to one of ordinary skill in the art.
The amount of release controlling triglyceride to be used will be determined based on the desired drug release rate.
As used herein, the term "diluents" or "fillers" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of dosage form. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol and starch and other materials known to one of ordinary skill in the art.
As used herein, the term "binders" is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, compressible sugar, gelatin, liquid gluclose, hydrocymethylcellulose, polyvinyl pyrrolidone and pregelatinized starch and other materials known to one of ordinary skill in the art.
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As used herein, the term "glidants" is intended to mean agents used in capsule formulations to improve flow of powder or pellets during capsule filling process. Such compounds include, by way of example and without limitation, colloidal silica, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel and other materials known to one of
ordinary skill in the art.
As used herein, the term 'plasticizer' includes all the compounds capable of plasticizing of softening of triglyceride used in invention. The plasticizer should be able to lower the melting temperature of the triglyceride. Plasticizers, such as PEG 6000 / Glyceryl monopalmetostearate / Glyceryl monostearate are included.
The following example is provided to further exemplify the invention, and are not intended to limit the scope of invention.
Process for the preparation of the formulation is as under:
1. Sift Venlafaxine hydrochloride, diluents and binder through ASTM 40#
mesh and mix them
in a suitable mixer.
2. Granulate the powder mix from step one using purified water.
3. Extrude and spheronize the wet granules of step 2 to form pellets.
4. Dry the pellets of step 3 using suitable dryer.
5. Coat the pellets from step 4 with rate controlling glycerides using suitable coating machine.
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EXAMPLES
Example 1

S.No Ingredient Mg/Cap %w/w
1. Venlafaxine Hydrochloride 170.00 38.6
2. Microcrystalline Cellulose 173.20 39.4
3. Hydroxypropylmethylcellulose 6.80 1.5
4. Hydrogenated castor oil 70.00 15.9
5. Glyceryl monostearate 11.00 2.5
6. Talc 9.00 2.0
Total 440.00 99.9
Venlafexine hydrochloride, Microcrystalline cellulose and hydroxypropylmethylcellulose were passed through ASTM 40# mesh and mixed together. The resulting mixture was granulated using water. The resulting wet granules were extruded and spheronised to form pellets. The pellets were coated with rate controlling triglycerides to achieve sustained release.
The dissolution rate of the novel dosage form was determined in 0.1N HC1
using a USP Type II apparatus with a paddle speed of 75rpm, at 37±2°C. The results of these studies are shown in the Table 1.
Table 1: Dissolution profile of the Example 1 and comparative dissolution with innovator formulation

Time (hrs) Percent drug releasedO.lN HCl, (Torrentformulation) Percent drugreleased O.lN HCl, (innovatorformulation)
1 7 5.5
2 18.3 15.7
4 40.2 38.8
8 64.8 65.8
12 80.2 77.9
24 92.5 91.5
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Example 2

S.No Ingredient Mg/Cap % w/w
1. Venlafaxine Hydrochloride 170.00 38.6
2. Microcrystalline Cellulose 173.20 39.4
3. Hydroxypropylmethylcellulose 6.80 1.5
4. Hydrogenated castor oil 70.00 15.9
5. Polyvinyl pyrrolidone 11.00 2.5
6. Talc 9.00 2.0
Total 440.00 99.9
Venlafaxine hydrochloride, Microcrystalline cellulose and
hydroxypropylmethylcellulose were passed through ASTM 40# mesh and mixed together. The resulting mixture was granulated using water. The resulting wet granules were extruded and spheronised to form pellets. The pellets were coated with rate controlling triglycerides and polyvinylpyrrolidone.
The dissolution rate of the novel dosage form was determined in 0.1 N HCl using a USP Type II apparatus with a paddle speed of 75rpm, at 37±2°C. The results of these studies are shown in Table 2.
Table 2: Dissolution profile of the Example 1 and comparative dissolution with innovator formulation

Time (hrs) Percent drug released95.1 N HCl, (Torrentformulation) Percent drug released95.1 N HCl, (innovatorformulation)
1 7 10
2 18.3 23.7
4 40.2 39.2
8 64.8 68.5
12 80.2 79.2
24 92.5 94.0
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Example 3

S.No Ingredients mg/cap % w/w
1. Venlafaxine HCL 170.00 34
2. Microcrystalline cellulose 167.50 33.5
3. HPMCK4M 2.50 0.5
4. Hydrogenated castor oil 150.00 30
5. Talc / magnesium stearate 10.00 2
6. Methanol* q.s. .
7. methylene chloride* q.s.
Total 500.00 100
Does not remain in final product
Venlafaxine hydrochloride, Microcrystalline cellulose and
hydroxypropylmethylcellulose were passed through ASTM 40# mesh and mixed together. The resulting mixture was granulated using water. The resulting wet granules were extruded and spheronised to form pellets. The pellets were coated with rate controlling triglycerides and polyvinylpyrrolidone. The coated pellets were mixed with talc and filled into hard gelatin capsules.
The dissolution rate of the novel dosage form was determined in 0.1N HCl using a USP Type II apparatus with a paddle speed of 75rpm, at 37±2°C. The results of these studies are shown in Table 3.
Table 3: Dissolution profile of the Example 3 and comparative dissolution with innovator formulation

Time (hrs) Percent drug released0.1N HCl, (Torrentformulation) Percent drug released95.1 N HCl, (innovatorformulation)
1 7 11
2 18.3 25.8
4 40.2 37.3
8 64.8 63.3
12 80.2 78.3
24 92.5 93.6
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Example 4

S.No Ingredients mg/cap % w/w
1. Sugar spheres 118.75 23.75
2. Ethylcellulose 10.00 2
3. HPMC 1.25 0.25
4. Venlafaxine HCL 170.00 34
5. PVP or HPMC 25.00 5
6. Colloidal silicone dioxide 15.00 3
7. Hydrogenated castor oil 150.00 30
8. Talc 10.00 2
9. Methanol* q.s. -
10. methylene chloride* q.s. -
Total 500.00 100
95. Does not remain in final product
Ethyl cellulose and HPMC were dissolved in methanol and methylene chloride. This solution was coated on sugar spheres using fluid bed coater. Venlafaxine hydrochloride, hydroxypropylmethylcellulose are dissolved in methanol and methylene chloride and Colloidal silicone dioxide was dispersed in the above drug solution. The resulting solution was coated on coated sugar spheres using fluid bed coater. The resulting drug coated pellets were coated with hydrogenated castor oil dissolved in methylene chloride in fluid bed coater. The coated pellets were mixed with talc and filled into hard gelatin capsules.
The dissolution rate of the novel dosage form was determined in 0.1N HCl using
a USP Type II apparatus with a paddle speed of 75rpm, at 37±2°C. The results of these studies are shown in Table 4.
Table 4: Dissolution profile of the Example 4 and comparative dissolution with innovator formulation

Time (hrs) Percent drug released95.1 N HCl, (Torrentformulation) Percent drug released95.1 N HCl, (innovatorformulation)
1 7 09
2 18.3 20.2
4 40.2 39.4
8 64.8 62.5
12 80.2 75.3
24 92.5 95.6
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CLAIMS:
1. Sustained release pharmaceutical formulation comprising a multiparticulate comprising Venlafaxine or a pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, and may further include one or more pharmaceutically acceptable excipients, which is further coated with a rate controlling glyceride.
Dated this on 18 June 2005.

KETANA BABARIA
Patent-Aid.com
For & on behalf of the Applicant
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ABSTFIACT
The present invention relates to sustained release pharmaceutical
formulation of Venlafaxine, which gives predictable drug release over an extended period of time. Extended release of the present invention is
ensured using release controlling triglyceride. Further, present invention also relates to a process for preparing said dosage form.
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