Field of the Invention

The present invention relates to an improved solid oral pharmaceutical compositions of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol and process for their preparation thereof.

Background of the invention

RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol is a major metabolite of l-[2-dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol. As a selective serotonin and norepinephrine reuptake inhibitor, RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol is currently approved for the treatment of major depressive disorder.

RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol is a weakly basic drug having good solubility in gastric pH conditions than at intestinal pH conditions.

RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol is represented by the following structural Formula-1.

RS-4-[2-dimethylamino-1 -(1 -hydroxycyclohexyl)ethyl]phenol is currently marketed in the U.S. under the brand name of Pristiq in the form of extended release tablets containing 50 mg and 100 mg of the drug, for oral administration.

RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol was exemplified as fumerate salt in U.S. Patent No.4,535,186. However the fumerate salt of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol has unsuitable physicochemical and permeability characteristics. RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl] phenol is also exemplified as free base in International publication WO 00/32555.

The succinate salt of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl] phenol has been described in U.S. patent number 6,673,838. The succinate monohydrate form of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol has been incorporated into an extended release hydro-gel tablet, which reduces adverse effects such as nausea, vomiting, diarrhea, and abdominal pain. Formulations of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol succinate describing the use of hydroxypropyl methylcellulose (HPMC) as the hydrogel matrix have been described in WO 02/064543.

Dosage form of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol is not available in the market.

Improved pharmaceutical composition of the present invention uses RS-4-[2- dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol.

It eliminates one step in the manufacturing of active pharmaceutical ingredient and so reduces the cost of the active pharmaceutical ingredient and hence the final cost of the finished goods and making it
affordable. The present invention provides for extended release formulations of RS-4-[2- dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol having comparable dissolution profile with that of innovator formulation. RS-4-[2-dimethylamino-l-(l-
hydroxycyclohexyl) ethyl]phenol has poor water solubility and hence exhibits poor dissolution in the media. RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol having good solubility in gastric pH conditions than at intestinal pH conditions. After oral administration, extended release tablet of RS-4-[2-dimethylamino-l-(l-hydroxycyclo hexyl)ethyl]phenol encounters variable pH conditions throughout the gastrointestinal tract i.e., from acidic to alkaline. In order to release the drug uniformly throughout the gastrointestinal tract in solubilized form, the present invention uses succinic acid in the tablet formulation, which creates acidic microenvironment for the RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol and helps in the solubilization, hence releases the drug uniformly throughout the gastrointestinal tract.

In accordance with the present invention, gastro-retentive extended release tablets of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol were developed with the intention of increasing the therapeutic efficacy. Gastro-retentive ER tablets of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyljphenol remains in the confines of the stomach for prolonged periods of time because of its buoyancy character and releases most of the drug in the gastric region. As a result, drug released from the dosage form will be exposed to gastric pH conditions, where it has more solubility, and therefore the drug will be available in the solution form for absorption.

The present invention provides extended release tablet formulations of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol omposition having comparable dissolution profile with that of innovator formulation i.e., Pristiq®.

Summary of the invention:

The present invention relates to an improved solid oral pharmaceutical composition of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol compound of formula-1 and also relates to the manufacturing process for the same.

The first aspect of the present invention related to the solid oral pharmaceutical composition comprising of:

a) RS-4-[2-dimethylamino-1 -(1 -hydroxycyclohexyl)ethyl]phenol;

b) succinic acid with or without tartaric acid;

c) one or more release-controlling agents;

d) one or more fillers/diluents;

e) optionally one binding agent;

f) at least one glidant;

g) at least one lubricant and h) optionally coating agent.

The further aspect of the present invention relates to the solid oral pharmaceutical composition comprising of:

a) RS-4-[2-dimethylamino-1 -(1 -hydroxycyclohexyl)ethyl]phenol;
b) succinic acid;

c) one or more release-controlling agents ;

d) one or more fillers/diluents;

e) at least one glidant;

f) at least one lubricant

g) optionally one binding agent;

h) optionally one alkaline agent and i) optionally coating agent.

The second aspect of the present invention relates to the process for the preparation of solid oral pharmaceutical composition of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol.

Detailed description of the invention:

The present invention relates to an improved solid oral pharmaceutical
composition of RS-4-[2-dimethylamino-1 -(1 -hydroxycyclohexyl)ethyl]phenol compound of formula-1 and also relates to the manufacturing process for the same.

Herein the term used "an improved solid oral pharmaceutical compositions" refers to "extended release pharmaceutical composition" that achieves sustained release of active ingredient over extended period of time.

The first aspect of the present invention provides an improved solid oral pharmaceutical composition of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol comprising:

a) RS-4-[2-dimethylamino-1 -(1 -hydroxycyclohexyl)ethyl]phenol;
b) succinic acid with or without tartaric acid;

c) one or more release-controlling agents;

d) one or more fillers/diluents;

e) optionally one binding agent;

f) at least one glidant;

g) at least one lubricant; and

h) optionally coating agent.

The preferred embodiment of the present invention provides an improved solid oral pharmaceutical composition comprises of:

a) RS-4-[2-dimethylamino-1 -(1 -hydroxycyclohexyl)ethyl]phenol;

b) succinic acid;

c) microcrystalline cellulose;

d) hydroxypropylmethyl cellulose or carbopol or mixture thereof;

e) polyvinyl pyrrolidone;

f) lactose monohydrate;

g) talc;

h) magnesium stearate;

i) instacoat white.

The further embodiment of the present invention provides an improved solid oral pharmaceutical composition comprises of:

a) RS-4-[2-dimethylamino-1 -(1 -hydroxycyclohexyl)ethyl]phenol;

b) succinic acid;

c) one or more release-controlling agents;

d) one or more fillers/diluents;

e) at least one glidant;

f) at least one lubricant;

g) optionally one alkaline agent;

h) optionally one binding agent and

i) optionally coating agent.

The preferred embodiment of the present invention provides an improved solid oral pharmaceutical composition comprises of:

a) RS-4-[2-dimethylamino-1 -(1 -hydroxycyclohexyl)ethyl]phenol;

b) succinic acid;

c) microcrystalline cellulose;

d) hydroxypropylmethyl cellulose or xanthan gum or sodium carboxymethyl cellulose or mixture thereof;

e) polyvinyl pyrrolidone;

f) sodium bicarbonate

g) lactose monohydrate;

h) talc;

i) magnesium stearate;

j) instacoat white.

As used herein the term "release-controlling agent" refers to slow dissolving water soluble/swellable polymers or mixtures thereof. Examples of water soluble polymers include, but are not limited to, one or more of cellulose derivatives, gums, carboxyvinyl polymer, 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 carboxyvinyl polymer, vinyl alcohol or vinylpyrrolidone-based polymers may include one or more of carbopol, polyvinyl alcohol, polyvinylpyrrolidone and mixtures thereof. Particular preference according to the invention is the use of hydroxypropylmethyl cellulose (hypromellose) and carbopol. In a preferred embodiment, the release controlling agent may be present in the amount of 1 to 50% w/w of the composition; preferably the release controlling agent may be present in the amount of 5 to 45% w/w of the composition.

As used herein the term "filler/diluent" refers to the group selected from polyols such as mannitol, xylitol, sorbitol; lactose monohydrate, polysaccharides such as dextrates, maltodextrin and cyclodextrins; dibasic calcium phosphate, kaolin, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate mixtures thereof. Particular preference according to the present invention is given to use of microcrystalline cellulose and lactose monohydrate. The filler may be present in the amount of 2 to 45% w/w of the composition, preferably the filler may be present in the amount of 3 to 40% w/w of the composition, and most preferably the filler may be present in the amount of 5 to 35% w/w of the composition.

As used herein the term "binding agent" refers to the group consisting of corn starch, cellulose powder, crystalline cellulose, microcrystalline cellulose and light anhydrous silicic acid, polyvinyl pyrrolidone (povidone), vinylpyrrolidone- vinylacetate copolymer (copovidone) and cellulose derivatives like hydroxy methylcellulose, hydroxy ethylcellulose, hydroxy propylcellulose and hydroxy propylmethylcellulose and mixture thereof. Particular preference according to the present invention is given to use of polyvinyl pyrrolidone. The binding agent may be present in the present in the amount of 0.5 to 5% w/w of the composition, preferably the amount of 1 to 4.5% of the composition, most preferably in the amount of 1.3 to 4% w/w of the composition.

As used herein the term "lubricant" refers to the group selected from fatty acids and their salts such as magnesium stearate, calcium stearate and sodium stearyl fumarate; vegetable oils such as com oil, mineral oils; polyethylene glycols such as PEG-4000 and PEG-6000; mineral salts such as talc; inorganic salts such as sodium chloride; organic salts such as sodium benzoate, sodium acetate, and sodium oleate and polyvinyl alcohols. Particular preference according to the present invention is given to use of magnesium stearate. The lubricant may be present in the amount of 0.1 to 1% w/w of the composition; most preferably the lubricant may be present in the amount of 0.2 to 0.9% w/w of the composition.

As used herein the term "glidant" refers to the group selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, talc. Particular preference according to the present invention is given using talc. The glidant may be present in the amount of 0.1 to 2.5% w/w of the composition; preferably the glidant may be present in the amount of 0.5 to 2% w/w of the composition.

The second aspect of the present invention provides the manufacturing process for the preparation of an solid oral pharmaceutical composition of RS-4-[2-dimethylamino-l-(1 -hydroxycyclohexyl)ethyl]phenol.

Another aspect of the present invention provides the process for the extended release pharmaceutical composition of RS-4-[2-dimethylamino-l-(l-hydroxycyclo hexyl)ethyl]phenol comprises the steps of:

a) Sifting of the active ingredient RS-4-[2-dimethylamino-l-(l-hydroxy cyclohexyl) ethyl]phenol;

b) dissolving at least one binding agent in a suitable solvent;

c) blending the sifted active ingredient with succinic acid and at least one diluent;

d) granulating the dry mix of step-c) with binder solution of step-b);

e) drying of the resulting wet granulate;

f) milling and sifting of the dried granules ;

g) blending of the dried, sifted granules with one or more release-controlling agents; at least one glidant; one or more diluents; optionally one alkaline agent;

h) lubrication of the step-g) blend with at least one lubricant; i) compressing the final blend of step-h) into tablets; j) optionally coating the tablets.

Wherein in step-b) the suitable solvent is selected from water, alcoholic solvent such as ethanol, isopropyl alcohol and mixtures thereof.

Further aspect of the present invention provides the process for the extended release pharmaceutical composition of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol comprising of:

a) Sifting of the active ingredient RS-4-[2-dimethylamino-l-(l-hydroxy cyclohexyl) ethyljphenol;

b) dissolving at least one binding agent in a suitable solvent;

c) blending the sifted active ingredient with at least one diluent;

d) granulating the dry mix of step-c) with binder solution of step-b);

e) drying of the resulting wet granulate;

f) milling and sifting of the dried granules ;

g) blending of the dried, sifted granules with one or more release-controlling agents; succinic acid; at least one glidant; one or more diluents; optionally one alkaline agent;

h) lubrication of the step-g) blend with at least one lubricant; i) compressing the final blend of step-h) into tablets; j) optionally coating the tablets.

Wherein in step-b) the suitable solvent is selected from water, alcoholic solvent such as ethanol, isopropyl alcohol and mixtures thereof.

The composition of the present invention can be prepared by carrying out by the known process involving, the particular techniques of granulation via wet or dry route, via fusion or via direct tabletting for the formation of tablets, most preferably wet granulation technique.

The dosage form may be in tablet or capsule form or pellets, however, the tablet form is particularly suitable. The tablets may further be coated. For coating, any. formulation, which is customary in pharmaceutical technology, such as, for example, Insta coat white, opadry white, opadry pink, opadry green and like.

The extended release properties of the compositions of the present invention may be demonstrated by monitoring the dissolution of the RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol pharmaceutical compositions. The dissolution of the RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol pharmaceutical composition may be monitored using standard procedures well known in the art. For example, the dissolution test procedures such as the rotating basket method or paddle method or reciprocating cylinder or flow-through cell were disclosed in the U.S.

those in which the formulation is immersed in a suitable medium, for example an aqueous medium such as water, 0.9 % NaCI in 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 released RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol using standard methodology. In a particular embodiment dissolution tests were conducted on the extended release of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol tablets as obtained by the procedure described in the examples 4 and 8.

The results as in Table 17 and 18 illustrate that, the use of succinic acid and release controlling agent as per the formulae of Examples 4 & 8 help in achieving extended release RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol tablets which exhibit an equivalent dissolution profile to that of Pristiq.

In one of the embodiment of the present invention provides the process for the preparation of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol succinate by micronizing the mixture of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl] phenol and pre-milled succinic acid.

The process for the preparation of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol is disclosed in US 4,535,186 which is incorporated as reference.

The present invention is illustrated by the examples which follow various other embodiments and will become apparent to the skilled person from the present specification. However it is expressly pointed out that the examples and description are intended solely as an illustration and should not be regarded as restricting the present invention.

Examples: Examples of ER Tablets:

Example-1:

Table-1

Process:

All of the ingredients are sieved RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol was dry mixed with succinic acid, hypromellose, microcrystalline cellulose and talc in a mixer. The resultant mixture was then wet granulated with purified water and dried. The resulting mixer was blended with hypromellose and talc. Lubricating the above mixture with magnesium stearate. The mixture was then compressed into tablets.

The extended release tablet prepared by the above process was further coated with insta coat white.

Example 2:

Table-2

Process:

All of the ingredients are sieved RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyljphenol was dry mixed with succinic acid, tartaric acid, hypromellose, microcrystalline cellulose and talc in a mixer. The resultant mixture was then wet granulated with purified water and dried. The resulting mixture was blended with hypromellose and talc. Lubricating the above mixture with magnesium stearate. The mixture was then compressed into tablets. The extended release tablet prepared by the above process was further coated with insta coat white. Example 3:

Process:

All of the ingredients are sieved RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol was dry mixed with succinic acid, tartaric acid, carbopol, microcrystalline cellulose and talc in a mixer. The resultant mixture was then wet granulated with purified water and dried. The resulting mixture was blended with carbopol and talc. Lubricating the above mixture with magnesium stearate. The mixture was then compressed into tablets. The extended release tablet prepared by the above process was further coated with instacoat white.

Example-4:

Table-4

Manufacturing Process:

1. Sifted RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol, microcrystalline cellulose and succinic acid and transferred them into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Hydroxy propyl methyl cellulose, microcrystalline cellulose, lactose and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

Example-5:

Table-5

Manufacturing Process:

1. Sifted RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol, microcrystalline cellulose and transferred them into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Hydroxy propyl methyl cellulose, succinic acid, microcrystalline cellulose, lactose and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

ExampIe-6:

Table-6

Manufacturing Process:

1. Sifted RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol, microcrystalline cellulose, carbopol 912G and succinic acid and transferred into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Carbopol 971G, microcrystalline cellulose, lactose and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

Example-7:

Table-7

Manufacturing Process:

1. Sifted RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol, microcrystalline cellulose and transferred into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Carbopol 912G, Carbopol 971G, Microcrystalline cellulose, succinic acid, lactose and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

Examples of Gastro-rententive ER Tablets:

Example-8:

Table-8

Manufacturing Process:

1. Sifted RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyljphenol, microcrystalline cellulose, and succinic acid and transferred them into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Hydroxypropyl methyl celluloses, sodium bicarbonate, lactose and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

Example-9:

Table-9

Manufacturing Process:

1. Sifted RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol, microcrystalline cellulose, and transferred them into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Hydroxypropyl methyl cellulose, succinic acid, lactose, sodium bicarboante and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

Example-10:

Table-10

Manufacturing Process:

1. Sifted RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol, microcrystalline cellulose, and succinic acid and transferred them into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium bicarbonate, lactose and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

Example-11: Table-11

Manufacturing Process:

1. Sifted RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol, microcrystalline cellulose, and transferred them into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium bicarbonate, succinic acid, lactose and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

Example-12:

Table-12

Manufacturing Process:

1. Sifted RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol, microcrystalline cellulose, and succinic acid and transferred them into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Xanthan gum, sodium carboxymethyl cellulose, sodium bicarbonate, lactose and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

Example-13:

Table-13

Manufacturing Process:

1. Sifted RS-4- [2-dimethylamino-1 -(1 -hydroxycyclohexyl) ethyl]phenol, microcrystalline cellulose, and transferred them into rapid mixture granulator (RMG) and mixed.

2. Polyvinylpyrrolidone was dissolved in purified water.

3. Dry mix obtained in step-1 was granulated by using step-2 binder solution in RMG.

4. Resultant wet granulate from step-3 was dried and then sifted.

5. Xanthan gum, sodium carboxymethyl cellulose, sodium bicarbonate, succinic acid, lactose and talc were sifted and mixed with step-4 granules.

6. The blend obtained in step-5 was lubricated with sifted magnesium stearate.

7. The final blend obtained in step-6 was compressed into tablets and coated with instacoat white.

Test Example-1: Stability Test:

The Extended release tablets of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl]phenol of example-4 were evaluated for stability as per ICH guide lines. Results of the extended release tablets stored at 40°C and 75%RH for 1st, 2nd, 3rd & 6th months are given below.

Table-14

The gastric retentive extended release formulation of RS-4-[2-dimethylamino-l-(1-hydroxycyclohexyl) ethyl]phenol of example-8 were evaluated for stability as per ICH guide lines. Results of the gastric retentive extended release tablets stored at 40°C and 75%RH for 1st, 2nd , 3rd & 6th months are given below.

Test Example-2: Dissolution Profile Test:

Dissolution studies were carried out with tablets of Example-4 & Example-8 of the present invention and innovator formulation (Pristiq).

Table-16 shows the comparative dissolution profile of Example-4 and Pristiq. Based on the dissolution profile, pharmaceutical composition of the present invention is having uniform dissolution pattern as that of innovator and it is expected that pharmaceutical composition of the present invention to show similar activity in the treatment of major depressive disorder.

Comparative dissolution profile of Example-4 (50mg) of the present invention and Pristiq (50mg):

Dissolution medium: 900ml of 0.9% Sodium chloride solution Dissolution apparatus: USP type-I, 100RPM

Table-17 shows the comparative dissolution profile of Example-8 and Pristiq. Based on the dissolution profile, pharmaceutical composition of the present invention is having uniform dissolution pattern as that of innovator and it is expected that pharmaceutical composition of the present invention to show similar activity in the treatment of major depressive disorder.

Comparative dissolution profile of Example-8 (50mg) of the present invention and Pristiq (50mg):

Dissolution medium: 900ml of 0.1 N Hydrochloric acid solution Dissolution apparatus: USP type-1,100RPM

Example-14: Process for the preparation of RS-4-[2-dimethylamino-l-(l-hydroxy cyclohexyl)ethyl]phenol Succinate:

Succinic acid (44.8 g) was milled and passed through 40 mesh. RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl]phenol (100 g) was added to the pre-milled succinic acid and stirred for 45 minutes in rotary cone vacuum drier at 25° to 35°C. Micronized the obtained RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl)ethyl] phenol succinate.

Yield: 144.8 g

PSD: D 0.5: NMT 2.0u and D 0.9: NMT 90.0µ

We Claim:

1. The pharmaceutical composition for the treatment of major depressive disorder comprising of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl] phenol, succinic acid, one or more release controlling agents, one or more fillers/diluents, at least one binding agent, at least one glidant, at least one lubricant, optionally alkaline agent and optionally coating agent.

2. The pharmaceutical composition of claim 1, wherein

a) The release-controlling agent is water soluble/swellable polymer;

b) the binding agent is selected from polyvinylpyrrolidone, cellulose powder, corn starch, copovidone or mixtures thereof;

c) the diluents are selected from microcrystalline cellulose, lactose or mixtures thereof;

d) the lubricant is selected from magnesium stearate, calcium stearate, vegetable oils;

e) the alkaline agent is selected from alkaline carbonates, alkaline bicarbonates or mixtures thereof;

f) the glidant is selected from talc, colloidal silicon dioxide, calcium silicate and magnesium silicate and silicon hydrogel;

g) the coating agent is selected from instacoat white, opadry white, opadry pink and opadry green.

3. The pharmaceutical composition of claim 2, wherein the water soluble polymer may be a cellulose derivative selected from hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose or mixtures thereof; or a gum selected from xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate and mixtures thereof; or a vinylpyrrolidone-based polymer selected from carbolpol, polyvinyl alcohol or mixtures thereof.

4. The pharmaceutical composition of claims 1 & 2, the alkaline agent is sodium bicarbonate.

5. The pharmaceutical composition for the treatment of major depressive disorder comprising of RS-4-[2-dimethylamino-l-(l-hydroxy cyclohexyl) ethyl]phenol; succinic acid; polyvinyl pyrrolidone; microcrystalline cellulose; lactose; release-controlling agents selected from hydroxy propylmethyl cellulose, xantan gum, carbopol, sodium carboxymethyl cellulose or mixtures thereof; talc; magnesium stearate and coating is instacoat white.

6. The pharmaceutical composition for the treatment of major depressive disorder comprising an effective amount of RS-4-[2-dimethylamino-l-(l-hydroxy cyclohexyl)ethyl]phenol; succinic acid; polyvinyl pyrrolidone; microcrystalline cellulose, lactose; release-controlling agents selected from hydroxy propylmethyl cellulose, xanthan gum, carbopol, sodium carboxymethyl cellulose or mixtures thereof; sodium bicarbonate; talc; magnesium stearate and coating is instacoat white.

7. The pharmaceutical composition for the treatment of major depressive disorder of any of the preceding claims is extended release pharmaceutical composition.

8. A method for preparation of an extended release pharmaceutical composition for the treatment of major depressive disorder comprising of:

a) Sifting of the active ingredient RS-4-[2-dimethylamino-l-(l-hydroxy cyclohexyl) ethyljphenol;

b) dissolving at least one binding agent in a solvent;

c) blending the sifted active ingredient with succinic acid and at least one diluent;

d) granulating the dry mix of step-c) with binder solution of step-b);

e) drying of the resulting wet granulate;

f) milling and sifting of the dried granules;

g) blending of the dried, sifted granules with one or more release-controlling agents; at least one glidant; one or more diluents; optionally one alkaline agent;

h) lubricating the blend of step-g) with at least one lubricant;

i) compressing the final blend of step-h) into tablets; j) optionally coating the tablets.

9. A method for the preparation of an extended release pharmaceutical composition for the treatment of major depressive disorder comprising of:

a) Sifting of the active ingredient RS-4-[2-dimethylamino-l-(l-hydroxy cyclohexyl) ethyl]phenol;

b) dissolving at least one binding agent in a solvent;

c) blending the sifted active ingredient with at least one diluent;

d) granulating the dry mix of step-c) with binder solution of step-b);

e) drying of the resulting wet granulate;

f) milling and sifting of the dried granules ;

g) blending of the dried, sifted granules with one or more release-controlling agents; succinic acid; at least one glidant; one or more diluents; optionally one alkaline agent;

h) lubricating the blend of the step-g) with at least one lubricant; i) compressing the final blend of the step-h) into tablets; j) optionally coating the tablets.

10. An extended release pharmaceutical composition of any of the preceding claims is in the form of tablets or capsules.