NOVEL CONTROLLED RELEASE ORAL DOSAGE FORM OF ANTIDEPRESSANT AGENT AND PROCESS FOR PRODUCING THE SAME
TECHNICAL FIELD
This invention relates to controlled release pharmaceutical formulation of Fluoxelin its enantiomers and/or its pharmaceutical I y accepted salts for oral administration and process for producing them.
BACKGROUND OF INVENTION
Fluoxelin is a selective serotonin {5HT) reuptake inhibitor belonging to Arloxyphenyipropylamines general class of compounds. It is chemically (±)-N-Methyl-3-phenyl-3-[(alpha,a!pha,alpha-trifluoro-p-tQlyl)Qxy]propylamine and has molecular formula CI7-HI8-F3-N-O.CI-H. Therapeutically Fluoxelin belongs to the class of antidepressant, anliobesily and anxiolytics.
Fluoxelin as an antidepressant drug is disclosed in the U.S. Pat, No. 4,314,081, 4,626,549 and 5,847,214. The teaching for (S) and (R) enantiomeric forms of Fluoxelin are found in U.S. Pat. No. 5,889,186 and 5.356,934 respectively.
Fluoxelin is conventionally administered in the tablet, capsule or solution form under the brand name of SARAFEM or PROZAC {Eli Lilly and Company) in its hydrochloride salt. Fluoxelin's primary use in the treatment of depression which along with mania falls under the heading of affective disorder,
Fluoxelin is a racemic mixture or R-Fluoxetin and S-Fluoxelin enantiomers. Il is extensively metabolized in liver to Norfluoxetin and number of other unidentified melabolites. The only identified active metabolite Norfluoxetin is formed by demethylation of Fluoxelin. The primary route of administration appears to be hepatic metabolism.

The pulvule, tablet, oral solution dosage form and Prozac weekly capsule of Fluoxetin are bioequivalent. Food does not appear to affect the systemic bioavailability of Fluoxelin although it may delay its absorption for 1-2 hour which is probably not clinically significant. Thus Fluoxetin may be administered with or without food.
Fluoxetin has substantially slow elimination half life. After acute administration it has an elimination half life of 1 to 3 days and after chronic administration it has an elimination half life of 4 to 6 days. The Norfluoxetin has elimination half life of 4 to 16 days after acute and chronic administration. Prozac weekly capsules, a delayed release formulation, contain enteric coated pellets that resist dissolution until reaching a segment of the gastro intestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of Fluoxetin 1 to 2 hour relative to the immediate release formulations. Administration of Prozac Weekly once weekly results in increased fluctuations between peak and trough concentration of Fluoxetin and Norfluoxetin compared to once daily dosing. Average steady state Fluoxetin concentrations are approximately 50% lower following the once weekly regimen compared to the once daily regimen.
It is necessary therefore to decrease the peak and trough fluctuations and to attain the steady state level of Fluoxetin after administration to reduce the possible side effects and toxic effects while maintaining the same therapeutic effect of the dosing. The above aim is generally obtained by administration of the active ingredient in the form of dosage form which allows the controlled release of active ingredient over an extended period of time. The advantage to the patient and clinician in having consistent and uniform drug levels of the medication over an extended period of time are likewise recognized. Among the most important advantages of such controlled release formulations are: 1) Consistent and substantially uniform blood level over an extended period of time, 2) Increase and more efficient absorption for the drugs which have more specific absorption site, 3) The ability to reduce the number of dosage per period of time, 4) Minimizing or elimination of local and/or systemic side effects, 5) Improved efficiency and safety of treatment, 6) Reduced fluctuation of drug level and 7) Better patient compliance with overall disease management.

It is expected that by administering Fluoxetin in the dosage range of 60-120 mg in the form of controlled release formulation as described in the present invention will be able to maintain the blood level in therapeutically effective concentration for the period of 7 to
10 days.
EP 1027887 discloses the controlled release dosage form of antidepression agent or other low solubility drug that is spray dried or spray coated amorphous solid dispersion of the drug in an ionizable cellulosic polymeric matrix that is incorporated into secondary erodible polymeric matrix. Hov^ever, the present invention does not utilize such a spray drying, spray coating or solid dispersion technique to produce the controlled release formulation of present invention.
It is therefore, an objective of the present invention to prepare controlled release of Fluoxetin formulation suitable for oral administration.
11 is another object of the present invention to provide controlled release of Fluoxetin
formulation suitable for once every seven days to ten days of administration.
It is further objective of the present invention to ensure the uniformity of the release
pattern from said controlled release formulation of Fluoxetin. The said formulations are
in the range of 60-120 mg.
SUMMARY OF INVENTION
The controlled release matrix tablet formulation of present invention comprising
Pharmaceutical active agent, one or more rate controlling Polymer, Pharmaceutical
carrier such as binder, lubricant, diluent, optionally film coat.
In other embodiment, the controlled release formulation of present invention comprises a core comprising a active agent along with pharmaceutical carriers,coated with one or more rate controlling polymers, optionally contain separating layer between core and controlling layer.

DISCLOSURE OF IIVVENTION
The present invention discloses the controlled release formulation of Fluoxetin its enantiomers or its pharmaceutically acceptable salts suitable for oral administration, for the treatment of various depressive disorders known to the art.
The formulation of the present invention presented in the form of matrix tablet or mini tablets comprising Pharmaceutical active agent, one or more rate controlling Polymer, Pharmaceutical carrier such as binder, lubricant, diluent, optionally fdm coat.
The formulation is presented in the form of pluralities of particles including spherical, elliptical or cylindrical particles, tablets, mini-tablets or pellets coated with rate controlling polymer alone or in combination with two or more polymers, which allow release of Fluoxetin over an extended period of time. The formulation may comprise a blend of two or more populations of pluralities of particles, pellets or mini-tablets. Controlled release feature is added by coating the dosage form with the controlled release polymers known in the prior art. The said formulation may optionally contain the separating layer between the core and the controlled release polymer layer.
The formulation may also be present in the form of matrix tablet or mini tablets without the need of coating with rate controlling polymers to achieve the controlled release feature.
The formulation of the present invention presented in the form of matrix tablet or mini tablets comprising Pharmaceutical active agent, one or more rate controlling Polymer, Pharmaceutical carrier such as binder, lubricant, diluent, optionally film coat.
The matrix tablet formulation of the present invention is made accordance to the following steps:
1. Blending active agent and rate controlling polymer.
2. The resulatant blend was mixed with diluents.
3. Granulating the blend from step 2 with aqueous solution of binder.

4. Drying the wet granules at 60 C,
5. Blending the granules with lubricants.
6. The lubricated granules of the step 5 were compressed onto tablet.
The matrix tablet referred above contains Fiuoxetin. which is released in controlled manner over an extended period of time. While not wishing to be bound by any particular theory of delivery mechanism, the delivery from matrix tablet is believed to take place by the mechanism of diffusion or matrix erosion.
The controlled release formulation of present invention is in the form of pellet comprising A) a core comprising of active agent, pharmaceutical carrier B) coating layer comprising one or more rate controlling polymers.
The pellet formulation optinally contain separating layer between the core and controlled release polymer layer.
The active ingredient can be present as freebase or pharmaceutically acceptable salt, solvate, enanliomers or a mixture thereof. Further, the active ingredient, vi/here applicable, may be present either in the form of substantially optically pure enantiomers, or as a mixture, racemic or otherwise, of enantiomers. The present invention describe controlled release formulation in the dosage range of 60-120 mg ,more preferably 90 mg. The present invention provides controlled release of Fiuoxetin formulation suitable for once every seven days to ten days of administration.
In the present invention active agent fiuoxetin and rate controlling polymer is in the ratio of 0.5 to 0.75 preferably 1:0.55 more preferably 1:0.25.The polymer-to-polymer ratio (Methocel K lOOM: Methocel K. i5M) is in the ratio of 0 .5: 35 preferably 1:0.25 more preferably 1 :0. 19.

In the present invention the rate-controlling polymer consists of pharmaceutical I y acceptable water-soluble or water-insoluble polymers. Alternatively a mixture of rate controlling polymers may be used with an objective to release the drug over an extended period of time in controlled manner.
The rate controlling polymers are selected from the pharmaceutically accepted controlled release polymers like Eudragit L series e.g. Eudragit LlOO, Eudragit L 100-55, Eudragit L-30 D-55, the Eudragit S e.g. Eudragit SI00, the Eudragit NE series e.g. Eudragit NE 30D, the Eudragit RL series, e.g. Eudragit RL PO, Eudragit RL 30D, and the Eudragit RS series e.g. Eudragit RS PO, and Eudragit RS 30D; vinyl polymers like mixture of polyvinylpyrrolidone and polyvinyl alcohol, polyvinyl chloride; cellulose derivatives like hydroxypropyi melhylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, ethyicellulose; cellulose esters like cellulose acetate propionate; polysaccharides like chitosan, xanthan, dextran, alginic acid, sodium alginate; cremophor like Carbopol 974 P/971 P, polyethylene oxide or mixtures thereof.
The active ingredient can be present as free base or pharmaceutically acceptable salt, solvate, enantiomers or a mixture thereof Further, the active ingredient, where applicable, may be present either in the form of substantially optically pure enantiomers, or as a mixture, racemic or otherwise, of enantiomers.
Oral dosage form of the present invention can be in the form of Multiparticulate formulation or in the form of matrix or coated tablet. The term "Multiparticulate'' as described herein includes pluralities of particles comprising spherical, elliptical, cylindrical particles, pellets or mini-tablets and mixture or combinations thereof.
The controlled release formulation described above may contain the auxiliary pharmaceutically accepted excipients such as diluents, lubricants, surfactants, plasticisers, opacifying agents and such like. As will be appreciated by those skilled in the art, the exact choice of excipients and their relative amounts added will depend to some extent on

the final dosage form into which the controlled release Fluoxetin formulation is incorporated.
Suitable diluents as used in this description includes one or more cellulose derivatives comprising microcrystalline cellulose, powdered cellulose; one or more sugars comprising lactose, sucrose, glucose; one or more starch derivatives comprising com starch, potato starch, starch 1500; one or more poiyols comprising mannitol, xylitol, sorbitol; dicaicium phosphate and such like.
The lubricants of interest are stearic acid, colloidal silicon dioxide (Aerosil), magnesium stearale, calcium stearate, talc and such like.
The channeling agents include for example crosspovidone, corsslinked polyvinylpyrrolidone, corsslinked starch, sodium starch glycolate, crosscarmeilose, crosscarmellose sodium, sodium carboxymethyl cellulose and mixtures or combinations thereof
rhe surfactants used are preferably Tweens and sodium lauryl sulphate and the plasticisers are selected from any one of the following consisting of glycerol, triacetin, dibutyl sebocate, castor oil, diethyl pthalate, dibiityl pthalate, triethyl citvate or citrate esters, polyethylene glycol and such like.
■fhe smoothening coat may or may not be applied with negligible percentage of polymers with an object of providing a smooth surface for the subsequent controlled release coating. The optional smoothening coat can be applied using one or more of the agents like N-viny! pyrrolidone (PVP K-30/K-90), polyethylene glycol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium alginate, Eudragit RDIOO, combination of N-vinyl pyrrolidone and vinyl acetate (Plasdone S-630), Opadry AMB along with one or more pharmaceutically acceptable excipients like plasticisers i.e. triethyl citrate, polyethylene glycol, diethyl phthalate, dibutyl phthalate, glidants,

antiadherents like talc, magnesium stearate, kaolin, colloidal silicon dioxide, which are commonly known to those skilled in the art.
Process for controlled release coating is as follows:Dissolving Aquacoat ECD in purified water and triethyl acetate does the controlled release coating. The resulting solution is sprayed on the pellets, minitablet,and plurities of particles using fluidized bed . Aquacoat ECD .triethyl acetate can be replaced by functionally equivalent agent as described in the specification.
Fluoxetine hydrochloride controlled release tablet, 90 mg Example 1:

S.No, Ingredients Quantity in mg/Tablel
1 Fluoxetine hydrochloride 101.00
2 Plasdone S-630 35.00
3 MethocelKIOOM 21.00
4 MelhocelK15M 4.00
5 Avicel PH 102 278.00
6 Talc 2.00
7 Magnesium stearate 2.00
8 Aerosil 200 2.00
9 Purified water qs
Total 450,00
Film coal tine:
Opadry pink OY 54937 7,00
Total 457.00
Process of preparation:
A) Ingredient 1 was weighed and mixed with Ingredients 3 and 4 mixtures in
geometric dilution.
B) The resultant blend was mixed again in geometric dilution with ingredient 5.
C) Ingredient 2 was dissolved in purified water and the resulting powder blend of step B was granulated with Plasdone S-630 solution.
D) The wet mass was passed through 8 # and dried at 60 C and again passed through 30 #.
E) Ingredient 6,7and 8 were weighted and passed through 40 # and mixed with
granules of D step thoroughly.
F) The lubricated granules were compressed using 11 mm shallow concave punches.
Film coating process:

The Fluoxetine hydrochloride controlled release tablets, 90 mg were coated in perforated coating pan with opadry pink OY 54937 by aqueous coating method. Example 2:

S.No. Ingredients Quantity in mg /Tablet
1 Fluoxetine hydrochloride 101.00
2 Plasdone S-630 35.00
3 MethocelKlOOM 44.00
4 MethocelK15M 11.00
5 Avicel PH 102 248.00
6 Tate 2.00
7 Magnesium stearate 2,00
8 Aerosil 200 2.00
9 Purified water qs
Total 450.00
Film coating:
Opadrv pink OY 54937 7.00
Total 452.00
Process of preparation:
A) Ingredient 1 was weighted and mixed with Ingredients 3 and 4 mixtures in
geometric dilution.
B) The resultant blend was mixed again in geometric dilution with ingredient 5.
G) Ingredient 2 was dissolved in purified water and the resulting power blend of step
B was granulated with Plasdone S-630 solution. H) The wet mass was passed through 8 # and dried at 60 C and again passed through
30 #. I) Ingredient 6,7and 8 were weighted and passed through 40 U and mixed with
granules of D step thoroughly. J) The lubricated granules were compressed using I Imm shallow concave punches.
Film coating process:
The Fluoxetine hydrochloride controlled release tablets, 90 mg were coated in perforated coating pan with opadry pink OY 54937 by aqueous coating method.

Examp e3:
S.No. Ingredients Quantity in mg/Tablet
1 Fluoxetine hydrochloride 101,00
2 Eudraait RSPO 60.00
3 Plasdone S-630 27.00
4 Avicel PH 102 255.00
5 Talc 2.00
6 Magnesium stearate 3.00
7 Aerosil 812 2.00
Total 450,00

Process of preparation:
All the ingredients were weighted and passed through 40 U and mixed thoroughly and the blend was compressed into 11mm shallow concave tablet.

Examp e4:
rf^NfT Ingredients Quantity in mg/Tablet
M—^ Fluoxetine hydrochloride 101.00
2 Carbopol 97 IP 101.00
3 AvicelPH 102 175.00
4 Avicel PH200 _66m___5 Magnesium stearate Too"~ ^
6 Talc 2.00
7 Aerosil 812 2.00
Total 450.00
Process of preparation:
A) Ingredients 1 and 2 were weighted and mixed thoroughly.
B) ingredients 3 to 7 were weighted and passed through 40 # and this blend was mixed with blend of step A and compressed into 11mm shallow concave tablets.

Examp eS:
S.No. Ingredients Quantity in ms /Tablet
__[_l Fluoxetine hydrochloride 101.00
2 MethocelKlS M 37.50
3 Piasdone S-630 27.00
4 AvicelPH 102 240,00
5 Carbopol 97 IP 37.50
6 Magnesium stearate 3.00
_7 1 Tate 2,00
rg 1 Aerosil 812 2,00
Total 450,00
Process of preparation:
AH the ingredients were weighted and passed through 40 # and mixed thoroughly. This blend was compressed into 11 mm shallow concave tablet.

Examp e6:
S.No. Ingredients Quantity in mg /Tablet
1 Fluoxetine hydrochloride 101.00
2 Kollidon SR 40,00
3 Piasdone S-630 27.00
i±___ Avicel PH 102 275,00
5 Magnesium stearate 3.00
6 Talc 2.00
7 Aerosil 200 2.00
8 , Total 450.00

Process of preparation:
All the ingredients were weighted and passed through 40 # and mixed thoroughly. This blend was compressed into 11 mm shallow concave tablet.
Example 7.
S.No Ingredicnt(s) Quantity in mg /pellet
Core pellets
] Fluoxetine HCI iOI.O
2 Mannitol 255.0
"> J AvicelPH 101 23.0
4 Crosspovidone 6.0
5 Hydroxypropyl methyl cellulose, 5 cps 15.0
6 SLS 2.0
7 Purified water qs
402.0
Controlled release coating
9 Aquacoat ECD 64.75
10 Triethyl citrate 15.61
11 Purified water qs
483.0
Example 8.
S.No Ingredient(s) Quantity in mg / pellet
For core pellets
1 Fluoxetine HCI 101.0
2 Mannitol 255.0
3 AvicelPH 101 23.0
4 Crosspovidone 6.0
5 Hydroxypropyl methyl cellulose, 5 cps 15.0
6 SLS 2.0
7 Purified water qs
402.0
Controlled release coating
9 Aquacoat ECD 42.10
10 Tri ethyl citrate 10.14
11 Purified water qs
483.0

Evam pie 9.
S.No lngredi«nt(s) Quantity in
mn/pellet
For core pellets
I Fluoxetine HCI 101.0
2 Mannitoi 255.0
LJ AvicelPH 101 23.0
4 Crosspovidone 6.0
5 Hydroxypropy Im ethy i cellulose, 5 cps 15.0
6 SLS J^-^^-^^
7 Purified water _gs .
402.0
Controlled release coatin e
9 Eudrasit RS 30 D 42.10
10 Triethyl citrate _10J4__^J
n Purified water ^iLIZ3J
483.0
Dissolution profile of Fluoxetin controlled release formulation:
The formulation of the present invention was tested for the dissolution in different dissolution medias like O.IN HCL, pH 4.5 pthalate buffer, pH 6.8 phosphate buffer, using USP apparatus 1 100 RPM. The dissolution profile obtained is as follows. Formulation of Example 1:

TIME
INTERVAL
HOURS PERCENT DRUG RELEASED %
2 44
4 53
6 64
8 72
I 12 87

Formulation of Example 2:

TIME
INTERVAL
HOURS PERCENT DRUG RELEASED %
2 24
4 30
6 40
8 50
12 57
Thus the above dissolution profile show that the initial release of drug takes place when the medicament is in stomach. The drug release continues for the period of 12 to 16 hours with not more than 72% drug is release up to 8 hour period.
Stability profile: Formulation 1:

Time period

1 month 3 month

ASSAY 40°C/75%RH

98.6

100.3

Reference

RS (%Total impurity)

0.14

0.07

(%Maximum impurity)

0.07

0.04

Formulation 2:

Time period

1 month 3 montti

ASSAY 40°C/75%RH

98,1

99.2

Reference

RS (%Total impurity)

0,11

0.12

(%Maximum impurity)

0.02

0.07

Following examples given above are not limited to any particular formulation of controlled release Fluoxetin. Various modifications in the said formulation are obvious to those skilled in the art.

We claim:
1. A controlled release formulation comprising Pharmaceutically active agent, one or more rate controlling polymers along with pharmaceutical acceptable carriers,
2. A controlled release formulation of claim I wherein, tablet is matrix tablet or mini tablet.
3. A formulation according to claim I to 2 wherein, one or more rate controlling polymer selected from group consisting of Eudragit L series e.g. Eudragit LlOO, Eudragit L 100-55, Eudragit L-30 D-55, the Eudragit S e.g. Eudragit S100, the Eudragit NE series e.g. Eudragit NE 30D, the Eudragit RL series, e.g. Eudragit RL PO, Eudragit RL 30D, and the Eudragit RS series e.g. Eudragit RS PO, and Eudragit RS 30D; vinyl polymers like mixture of polyvinylpyrrolidone and polyvinyl alcohol, polyvinyl chloride; cellulose derivatives like hydroxypropyt methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose; cellulose esters like cellulose acetate propionate; polysaccharides like chitosan, xanthan, dextran, alginic acid, sodium alginate; cremophor like Carbopol 974 P/971 P, polyethylene oxide or mixtures thereof
4. A formulation according to claim I to 3 wherein, one or more diluent selected from group consisting of one or more cellulose derivatives comprising microcrystalline cellulose, powdered cellulose; one or more sugars comprising lactose, sucrose, glucose; one or more starch derivatives comprising com starch, potato starch, starch 1500; one or more polyols comprising mannitol, xylitol. sorbitol; dicalcium phosphate and such like.
5. A formulation according to claim I to 4 wherein, one or more lubricant selected from group consisting of stearic acid, colloidal silicon dioxide (Aerosil), magnesium stearate, calcium stearate, talc and such like.
6. A formulation according to claim 1 to 5 wherein, controlled release formulation comprises optionally film coating.

7. The formulation of any of claim 1 to 7 comprising

S.No. Ingredients Quantity in me/Tab iet
1 Fluoxetine hydrochloride 101.00
2 Plasdone S-630 35.00
3 MethocelKlOOM 21.00
4 MethocelKlSM 4.00
5 AvicelPH 102 278.00
6 Talc 2.00
7 Magnesium stearate 2.00
8 Aerosil 200 2.00
9 Purified water qs
Total 450.00
Film coatine;
Opadrv pink OY 54937 7.00
lotal 457.00
8. Process for the manufacturing of the controlled release matrix tablet formulation
comprising
a. Blending active agent and rate controlling polymer.
b. The resultant blend was mixed with diluents.
c. Granulating the blend from step 2 with aqueous solution of binder .
d. Drying the wet granules at 60 C.
e. Blending the granules with lubricants.
f The lubricated granules of the step 5 were compressed into tablet.
9. The controlled release formulation comprising a) a core comprising a active agent
b) coating layer comprising one or more rate controlling polymer.
10. The formulation according to claim 9 wherein, core comprises plurities of
particles as spherical, elliptical, pellets, or mini tablets.
11. The formulation according to claim 9 to 10 wherein, core comprises active agent further comprises diluent, binder lubricant, surfactant, and plasticezer,
12. The formulation according to claim 11 wherein, diluent selected from group consisting of one or more cellulose derivatives comprising microcrystalline cellulose, powdered cellulose; one or more sugars comprising lactose, sucrose, glucose; one or more starch derivatives comprising com starch, potato starch, starch 1500; one or more polyols comprising mannitol, xylitol, sorbitol; dicalcium phosphate and such like.

] 3. The formulation according to claim 11 wherein, binder selected from the group 14. The formulation according to claim 11 wherein, lubricant selected from the group
selected from group consisting of stearic acid, colloidal silicon dioxide (Aerosil),
magnesium stearate, calcium stearate, talc and such like. 15 .The formulation according to claim 11 wherein, surfactant selected from the
group used are preferably Tweens and sodium lauryl sulphate
16. The formulation according to claim U wherein, plasticezer selected from the
group are selected from any one of the following consisting of glycerol, triacetin,
dibulyl sebocate, castor oil, diethyl pthalate, dibutyl pthalate, triethyl citrate or
citrate esters, polyethylene glycol and such like.
17. The formulation according to claim 9 to 16 comprises optionally separating layer.
18. The formulation as any of claims I or 9 comprising fluoxetin hydrochloride,
19. The formulation of claim 9 to 16 comprising
S.No Ingredient(s) Quantity in|
me/pellet i
For core pellets
J Fluoxetine HCi IQl.Q
2 Mannitol 255.0
3 AvicelPHlOl 23,0
_4 Crosspovidone 6^0
5 Hydroxypropylmethyl 15.0
cellulose, 5 cps
6 SLS 2.0
^7 Purified water qs
402.0
Controlled release
coating _^
9 Aquacoat ECD 42.10
iO Triethyl citrate 10.14
11 Purified water qs
I I 483.0
20. The formulation of any of claim I or 9 wherein dosage form is in the range of 60-
120 mg, more preferably 90 mg,
21. The formulation of any of claim I or 9 wherein said formulation is suitable for once every seven days to ten days of administration.