F0RM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - ONCE DAILY EXTENDED RELEASE FORMULATIONS
COMPRISING DESVENLAFAXINE


2. Applicant(s)
(a) NAME :
(b) NATIONALITY:
(c) ADDRESS :
ALEMBIC LIMITED
An Indian Company.
Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed:
355 MUM 2009
18 FEB 2009

FIELD OF THE INVENTION
The present invention relates to extended release pharmaceutical composition comprising desvenlafaxine. Further, the present invention relates to process of preparing extended release pharmaceutical composition comprising desvenlafaxine.
BACKGROUND OF THE INVENTION
Depression is a psychiatric disorder that can be a primary condition or may co-exist with other mental, psychiatric or physical illnesses. Ivlany subtypes of depression have been described, including major depressive disorder, bipolar disorder, dysthymic disorder, adjustment disorder, seasonal affective disorder, premenstrual dysphoric disorder, postpartum depression, psychotic depression and atypical depression, among others. In general, these disorders are characterized by depressed mood, loss of interest or pleasure, feeling of guilt or low self-esteem, disturbances in sleep and-or appetite, low energy and poor concentration.
O-desmethylvenlafaxine or desvenlafaxine (ODV) are adopted names for the drug compound having a chemical name 1 -[2-dimethylamine(4-hydroxyphenyl)ethyl] cyclohexanol, and represented by structural Formula I.

Desvenlafaxine is prescribed for treating major depressive disorders. Desvenlafaxine, the major metabolite of venlafaxine, selectively blocks the reuptake of serotonin and norepinephrine and is currently marketed in the U.S. under the
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trademark PRISTIQ in the form of extended release tablets containing 50 mg and 100 mg of the drug, for oral administration.
Desvenlafaxine, chemically named 1-[2-(dimethylamino)-1-(4-phenol)ethyl]-cyclohexanol, was exemplified as a fumarate salt in U.S. Pat. No. 4,535,186. However, the fumarate salt of desvenlafaxine has unsuitable physicochemical and permeability characteristics. Desvenlafaxine is also exemplified as a free base in International Patent Publication No. WO 00/32555.
The succinate form of ODV has been described [U.S. Pat. No. 6,673,838]. The succinate monohydrate form of ODV has been incorporated into an extended release hydro-gel tablet, which reduces adverse effects such as nausea, vomiting, diarrhea, and abdominal pain. Formulations of desvenlafaxine succinate describing the use of hydroxypropyl methylcellulose (HPMC) as the hydrogel matrix have been described [WO 02/064543 A2].
Dosage form of Desvenlafaxine base is not available in the market. Desvenlafaxine base has poor water solubility and hence exhibits poor dissolution in the media. The present invention provides for extended release tablet formulations of desvenlafaxine base having excellent dissolution properties and which is equivalent to PRISTIQ®.
Therefore, there is stiff a need for the cfevefopment of the extended re/ease pharmaceutical composition comprising desvenlafaxine that can be prepared using a simple process.
SUMMARY OF THE INVENTION
In one general aspect there is provided an extended release pharmaceutical composition comprising:
a) desvenlafaxine base,
b) one or more pH modifiers,
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c) one or more release controlling agents and
d) optionally one or more other pharmaceutical excipients.
In yet another aspect there is provided a process for preparing an extended release pharmaceutical composition which comprises:
a) mixing desvenlafaxine, one or more pH modifiers and one or more release controlling agents,
b) granulating the mixture of step (a) with a binder solution,
c) drying, sifting the granules obtained in step (b) and further mixing with the extragranular excipients and
d) formulating the mixture into a suitable dosage form.
Embodiments of the extended release pharmaceutical composition comprise one or more of the following features. For example, the extended release tablet formulation comprises other pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients comprise one or more of binders, diluents, surfactants, lubricants/glidants, coloring agents, and the like.
The extended release pharmaceutical composition can be processed into a solid dosage form selected from a tablet, a capsule, sachet or a mini-tablet and the like.
DETAILED DESCRIPTION OF THE INVENTION
Generally provided herein is an extended release pharmaceutical composition comprising desvenlafaxine, having desirable release profiles, as well as process to prepare the same.
The phrase "extended release pharmaceutical composition" as used herein, includes solid dosage forms such as tablets, capsules, pills and like. For example, tablets can be prepared by techniques known in the art and contain a therapeutically effective amount of an active and such excipients as are necessary to form the tablet.

The phrase "extended release pharmaceutical composition" as used herein, includes any pharmaceutical composition that achieves slow release of active ingredient over an extended period of time, and includes prolonged, modified, extended and sustained-release compositions.
In a preferred embodiment, the present invention comprises 5-50 % w/w of desvenlafaxine, preferably the present invention comprises 10-40 % w/w of desvenlafaxine.
In another embodiment of the present invention, the extended release pharmaceutical composition comprises one or more pH modifier.
As used herein the term "pH modifier" refers to an organic or inorganic chemical material that is able to release hydrogen ions (acid), for example an organic or inorganic acid, an acidic polymer, e.g. a carbomer, or a latent acid, and which is generally pharmaceutically acceptable. A pH modifier is employed in the invention to shift the microenvironmental pH of the drug formulation to more acidic conditions. The term "microenvironmental pH" as used herein includes reference to the pH within and in the vicinity of the drug formulation. The composition may comprise one or more pH modifiers.
The pH modifier may be an acid, in particular a latent acid. Latent acids are compounds that hydrolyze to a free acid in presence of water, e.g., glucono-d-
lactone.
in yet another embodiment, the pH modifier can be acid anhydride.
The use of solid acids or pharmaceutical acceptable salts thereof as pH modifiers is particularly convenient for the manufacture of compositions according to the invention.
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In one embodiment of the invention, the pH modifier is an organic acid. Suitable organic acids contain one or more acidic groups, particularly compounds containing acidic groups selected from carboxylic and sulfonic acid groups, particularly those which are solid at ambient temperature, and especially those which have 2 or more acidic groups.
In another embodiment, the pH modifier is a water-soluble organic acid. Suitable water- soluble organic acids include but are not limited to organic acids selected from mono, di- or polybasic carboxylic acids and mono, di or tri-sulfonic acids, preferably those which are solid at ambient temperature. Particular solid water-soluble carboxylic acids include, for example mono or poly-carboxylic acids such as those containing from 1 to 20 carbon atoms, particularly from 2 to 6 carbon atoms, more particularly tricarboxylic acids containing from 4 to 6 and especially 4 carbon atoms, any of which acids may be saturated or unsaturated or having branched or non-branched carbon atom chains. Examples of suitable solid water-soluble mono-carboxylic acids include sorbic acid {2,4-hexandienoic acid). Examples of suitable solid water-soluble di-carboxylic acids include adipic, malonic, glutaric, maleic or fumaric acid. The carboxylic acids may be optionally substituted by one or more groups (for example 1, 2 or 3), which may be the same or different, selected from e.g. carboxy, amino or hydroxy. Suitable substituted solid water-soluble carboxylic acids include for example hydroxy substituted mono-carboxylic acids such as gluconic acid, solid forms of lactic acid, glycolic acid or ascorbic acid; hydroxy substituted di-carboxylic acids such as malic, tartaric, tartronic (hydroxymaionic), or mucic (galactaric) acid; tri-carboxylic acids, for example citric acid; or amino acids carrying an acidic side chain, such as glutamic acid or aspartic acid.
In another embodiment, the pH modifier is an aromatic carboxylic acid. Suitable aromatic carboxylic acids include water-soluble aryl carboxylic acids containing up to 20 carbon atoms.
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The pH modifier may comprise a polymeric organic acid. The polymer may be linear or branched or a combination thereof. Suitable polymeric acids include polymers containing a linear backbone with acidic groups, polymers containing a branched backbone with acidic groups, and mixtures thereof. Also of mention is alginic acid.
Preferentially the pH modifier is selected from an organic acid, an acidic polymer, and a latent acid.
Where the basic drug compound is desvenlafaxine, the pH modifier is preferably one selected from fumaric acid, aspartic acid, glutamic acid, adipic acid, cinnamic acid, ascorbic acid, ascorbyl palmitate, citric acid, sodium gutamine, malic acid, tartratic acid, L-lactic acid, maleic acid, oxalic acid, stearic acid, orotic acid, sebacic acid or, in each case, including mixtures thereof. More preferably are citric acid or ascorbic acid.
The composition is therefore preferably adapted such that its microenvironmentai pH is substantially maintained in at least a section of the Gl tract. The quantity and properties of the pH modifier should therefore be tailored to optimize absorption of the basic drug compound. This may involve the use of a pH modifier having a dissolution rate substantially similar to that of the basic drug compound and/or a sufficient quantity of pH modifier to maintain the microenvironmentai pH.
In a further embodiment, the pH modifier may be present in the amount 3-15% w/w of the composition.
In a further embodiment, the extended release pharmaceutical composition of the invention comprises one or more release controlling agents.
Examples of release controlling agents include water soluble/swellable polymers or mixtures thereof.
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Examples of water soluble polymers include, but are not limited to, one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone-based polymers and mixtures thereof. The cellulose derivatives may include one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The gums may include one or more of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate and mixtures thereof. The vinyl alcohol or vinylpyrrolidone-based polymers may include one or more of polyvinyl alcohol, polyvinylpyrrolidone and mixtures thereof.
In a preferred embodiment, the release controlling agent may be present in the amount 1-40% w/w of the composition, preferably the release controlling agent may be present in the amount 5-30% w/w of the composition.
The extended release pharmaceutical compositions may further comprise one or more non-functional coatings.
Non-functional coatings can facilitate in forming a smooth surface and better appearance of a pharmaceutical composition. Non-functional coatings can also help in overcoming common problems, including rupturing or cracking of release-controlling layers/membrane or fragmentation of the core due to mechanical stress generated during compression of cores into tablets or filling into capsules/sachets.
Coating solutions may be applied using techniques, for example, spray coating in a conventional coating pan or fluidized .bed processor or dip coating. Solutions or dispersions of polymers can be prepared in solvents, for example, dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof. Coating solutions may further comprise other pharmaceutically acceptable ingredients, for example, plasticizers, coloring agents and surfactants.
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The extended release pharmaceutical composition may also be formulated as granules filled into hard gelatin capsules or sachets, or formed into tablets.
The phrase 'pharmaceutically acceptable inert excipients," as used herein, includes all excipients used in the art of manufacturing solid dosage forms. Examples of pharmaceutically acceptable inert excipients include binders, diluents, surfactants, lubricants/glidants, coloring agents, and the like.
Suitable binders include, for example, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like, or mixtures thereof.
Suitable diluents include, for example, 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 or mixtures thereof.
Suitable surfactants include, for example, both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms.
Suitable lubricants/glidants include, for example, 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 one or more functional and/or non-functional layers comprising film-forming polymers, if desired, for e.g. Opadry.
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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 included within the scope of the present invention.
The extended release properties of the formulation of the present invention may be demonstrated by monitoring the dissolution of the active ingredient. The dissolution of the active ingredient may be monitored using standard procedures welt known to those skilled in the art (e.g. the dissolution test procedures, such as the Rotating Basket Method (Apparatus I) or Paddle Method (Apparatus II), disclosed in the U.S. Pharmacopeia (USP). Such procedures include those in which the formulation is immersed in an aqueous medium such as water or hydrochloric acid and aliquots of the medium are withdrawn at various time points over a period of 24 hours. The aliquots are analyzed using high pressure liquid chromatography (HPLC) with UV detection to determine the concentration of dissolved active ingredient using standard methodology. In a particular embodiment, the dissolution profile is determined by the Rotating Basket method by immersing a tablet in 900 ml of 0.9% NaCI solution in water at a speed of 100 rpm.
The example mentioned below demonstrates some illustrative procedures for preparing the extended release pharmaceutical composition as described herein. The example is provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention as defined by the claims.
Table 1: Example 1-3

Sr No. Ingredients Example 1 Example 2 Example 3

Quantity (mg/tablet) % w/w Quantity (mg/tablet) % w/w Quantity (mg/tablet) % w/w
1 O-Desmethy!
Venlafaxine
(Desvenlafaxine) 100.85* 28.81 50.42 14.41 50.31 29.59
2 Alginic acid 10.00 2.86 5.00 1.43 - ~
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3 Citric Acid monohydrate 15.00 4.29 10.00 2.86 - -
4 Methocel K100M CR 13.00 3.71 53.00 15.14 50 29.41
5 Microcrystalline cellulose (Avicel PH 101) 136.15 38.90 156.58 44.74 47.69 28.05
6 PVPK- 30 10.00 2.86 10.00 2.86 5 2.94
7 Isopropyl alcohol q.s. - q.s. - q.s. -
8 Purified Water q.s. - q.s. - q.s. -
9 Methocel K100M CR 62.00 17.71 62.00 17.71 15 8.82
10 Talc 2.00 0.57 2.00 0.57 1 0.59
11 Magnesium Stearate 1.00 0.29 1.00 0.29 1 0.59
Total weight of each tablet 350 mg 350 mg 170 mg
Process:
Desvenlafaxine, alginic acid, citric acid monohydrate, Methocel K100M CR and microcrystalline cellulose were weighed and sifted, mixed and transferred to rapid mixer granulator. PVPK-30 was dissolved in the mixture of Isopropyl Alcohol and Purified water and used for granulation of mixture of step I. After granulation the wet mass was sifted and dried. After drying, dried granules were sifted and mixed with Methocel K100M CR, talc and magnesium stearate and properly mixed.
This mixture was subjected to compression on rotary tablet compression machine by using suitable tooling.
The extended release tablet prepared by the above process was further coated with opadry.
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Dissolution studies data:
Apparatus: USP Type I - Basket, 100 rpm Media: 900 ml 0.9% NaCI in water Apparatus: USP type I (basket) Temperature: 37 + 0.5°C. RPM: 100
Table 2: Dissolution profile

Time Points (Hrs) % Release (Desvenlafaxine)
PRISTIQ® Example 1 Example 2 Example 3
1 15 17 19 2
2 24 25 28 3
4 37 37 43 7
8 58 59 62 15
12 71 72 75 25
24 89 87 90 53
F2 - 87 69 24
* Further when, a trial was taken without the use of the pH modifier (example 3), it was observed that the solubility of desvenlafaxine base in the media was poor. Based on the above similarity factor (F2 values), which need be greater than 50%, it was seen that the F2 value obtained for example 3 was below average.
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We Claim:
1. An extended release pharmaceutical composition comprising:
a) high solubility and low permeability drug,
b) one or more pH modifiers,
c) one or more release controlling agent and
d) optionally one or more other pharmaceutical excipients.
2. The extended release pharmaceutical composition according to claim 1, wherein
the high solubility and low permeability drug is desvenlafaxine.
3. The extended release pharmaceutical composition according to claim 1, wherein
the pH modifier is selected from the group comprising an organic or inorganic acid, an acidic polymer, or a latent acid or mixtures thereof.
4. The extended release pharmaceutical composition according to claim 1, wherein
the pH modifier is an organic acid.
5. The extended release pharmaceutical composition according to claim 1, wherein
the pH modifier is selected from citric acid, ascorbic acid, fumaric acid, adipic acid, maleic acid, alginic acid or mixtures thereof.
6. The extended release pharmaceutical composition according to claim 1, wherein
the rate controlling agent comprises one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone based polymers and mixtures thereof.
7. The extended release pharmaceutical composition according to claim 1, wherein
the rate controlling agent comprises one or more of ethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate, cellulose acetate phthalate, co-polymers of acrylate or methacrylate having a low quaternary ammonium content poly vinyl acetate or mixtures thereof.
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8. The extended release pharmaceutical composition according to claim 1, wherein one or more pharmaceutically excipients is selected from the group consisting of binders, diluents, surfactants, lubricants/glidants, coloring agents or mixtures thereof.
9. The extended release pharmaceutical composition according to claim 1, wherein the solid dosage form is selected from a tablet, a capsule, a sachet or a mini-tablet.
10. The extended release pharmaceutical composition according to claim 1, wherein the solid dosage form is tablet.
11. A process for preparing an extended release pharmaceutical composition which comprises:

a) mixing desvenlafaxine, one or more pH modifiers and one or more release controlling agents,
b) granulating the mixture of step (a) with a binder solution,
c) drying, sifting the granules obtained in step (b) and further mixing with the extragranular excipients and
d) formulating the mixture into a suitable dosage form.

12. The process for preparing an extended release pharmaceutical composition according to claim 10, wherein the pH modifier is selected from the group comprising of organic or inorganic acid, an acidic polymer, or a latent acid or mixtures thereof.
13. The process for preparing an extended release pharmaceutical composition according to claim 11, wherein the pH modifier is selected from citric acid, ascorbic acid, fumaric acid, adipic acid, maleic acid, alginic acid or mixtures thereof.
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14. The process for preparing an extended release pharmaceutical composition according to claim 10, wherein the rate controlling agent is selected from the group comprising of one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone based polymers and mixtures thereof.
15. The process for preparing an extended release pharmaceutical composition according to claim 13, wherein the rate controlling agent is selected from one or more of cellulose derivatives or mixtures thereof.
16. The process for preparing an extended release pharmaceutical composition according to claim 14, wherein the rate controlling agent is hydroxypropyl methyl cellulose.
17. An extended release pharmaceutical composition substantially as herein described and illustrated with respect to the examples.
18. The process for preparing an extended release pharmaceutical composition substantially as herein described and illustrated with respect to the examples.

Abhishek Sen Of S. Majumdar & Co. Applicant's Agent
Dated this 18th day of February 2009
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