FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
ENTERIC COATED COMPOSITION OF FLUOXETINE"
We, BA RESEARCH INDIA LIMITED, of BA Research House, Opposite "Pushparaj Towers", Nr. Judges Bungalows, Bodakdev, Ahmedabad-380 054, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention relates to a pharmaceutical composition for oral administration and in particular to an enteric coated composition of fluoxetine in the form of coated granules and/or pellets.
BACKGROUND OF THE INVENTION
Fluoxetine (N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine) is an antidepressant drug which is disclosed, for example, in U.S. Pat. Nos. 4,314,081 and 4,626,549. The action of fluoxetine is based on its capacity to selectively inhibit the uptake of serotonin by the neurons in the central nervous system. Fluoxetine is indicated in the U.S. and many other countries for the treatment of depression, obsessive-compulsive disorder, and bulimia.
The currently available pharmaceutical forms for fluoxetine, in the form of the hydrochloride salt, include capsules and a solution. A tableted formulation for compounds of the fluoxetine type is also contemplated in U.S. Pat. No. 4,314,081 (column 16, lines 52-55). More recently, a dispersible tablet has been disclosed (see EPO Patent application publication 693,281). A sustained release formulation of fluoxetine is claimed in U.S. Pat. No. 4,847,092. Tablets of serotonin uptake inhibitors which are coated to delay absorption and disintegration to "provide a sustained action over a longer period" are generally contemplated in U.S. Pat. No. 4,444,778.
There were, however, several difficulties in preparing enteric formulations of fluoxetine, as fluoxetine was found to react with many enteric coating polymers to form a slowly dissolving or even an insoluble coating.
In US Patent No. 5,910,319 the inventors, Anderson et al have described formulations for once per week dosing of higher doses (60 - 120ing) of fluoxetine without the attendant undesirable side effects. This has been achieved by developing an enteric coated pellet formulation of fluoxetine. This formulation uses hydroxy propyl methyl cellulose acetate succinate polymer as an enteric coat with or without the use of a non-reducing sugar, sucrose, as a separating layer. However, such a polymer is not only costly but also not easily available.
We herein describe an enteric coated formulation of Fluoxetine which uses readily available material, cheap and commercially viable.
EMBODIMENTS OF THE PRESENT INVENTION:
The present invention provides novel enteric compositions suitable for oral administration comprising: (a) a core comprising Fluoxetine or its pharmaceutically
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acceptable derivative thereof. The said core comprised of pharmaceutically inert nuclei and the fluoxetine or its salts mixed and compressed together, (b) an intermediate layer, and (c) an enteric layer; such that the said composition is substantially free of any alkaline reacting compounds.
Accordingly, it is an object of the present invention to provide a pharmaceutical composition and a process of manufacturing the same for the delayed release of antidepressant fluoxetine or its pharmaceutically acceptable derivative thereof.
Another object of the present invention is an enteric released solid pharmaceutical composition adapted for oral administration.
Yet another In yet embodiment is provided an enteric fluoxetine composition in a core formed by nuclei coated with an intermediate layer followed by an enteric layer.
DETAILED DESCRIPTION
The present invention provides novel enteric compositions suitable for oral administration comprising: (a) a core comprising therapeutically effective amount of Fluoxetine or its salts, the said core comprised of pharmaceutically inert nuclei and the Fluoxetine or its salts like HC1 mixed and compressed together, (b) an intermediate layer, and (c) an enteric layer; such that the fluoxetine used is substantially free of any alkaline reacting compound.
The term composition includes but not limited to solutions and/or suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro-tablets, capsules, pellets, comprising fluoxetine in a core constituted by nuclei and coated with intermediate layer/s followed by enteric layer.
The term "therapeutically effective amount" means an amount of the drug which is capable of eliciting a physiological response in a human patient. More specifically, the term "therapeutically effective amount" means the amount of drug, which is capable of treating depression and related psychotropic disorders.
The said medicament according to the present invention comprises a formulation substantially as herein described, and in particular a capsule or a tablet or micro-tablets or granules or pellets filled in capsule formulaton, typically an enteric or delayed release capsule formulation substantially as hereinafter further described.
Suitably a formulation according to the present invention provides a novel enteric dosage form, preferably capsules or micro-tablets in capsule form comprising core comprising pharmaceutically inert nuclei which is comprised of fluoxetine or its pharmaceutically acceptable derivative thereof and optionally one or more suitable excipients
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and the said core coated with intermediate layer/s followed by enteric layer and the process for preparing the same.
In a preferred embodiment of the present invention, the pharmaceutically inert nuclei, as the name may suggest, is composed of a substance or a mixture of such substances that are pharmaceutically inert and preferably do not interfere with the biological action of the fluoxetine or its salts. Preferable examples of such substances include lactose, dextrose, saccharose, starch and other sugars. A wide variety of other substances can also be used in developing the inert nuclei.
The said core is comprised of pharmaceutically inert nuclei and fluoxetine or its salts mixed and compressed together. The mixing here may be purely physical mixing, deposition, coating, adsorption, aggregation or adhesion and alike. Such a mixing of the said pharmaceutically inert nuclei and fluoxetine may be achieved in several different ways, including those already documented in the prior art. According to one of the embodiment of the invention, such a mixing is achieved by granulation, and preferably through fluidized bed granulation. Such processes results in formation of granules comprising pharmaceutically inert nuclei and fluoxetine, which are then compressed together.
In another embodiment of the invention, the said core may be prepared by contacting pharmaceutically inert nuclei with a medium containing fluoxetine, drying the product and subjecting the product to compression. Yet another way of preparing the said core could be by coating of the pharmaceutically inert nuclei with fluoxetine using one of the coating techniques generally known.
The present invention provides a process for the manufacture of a pharmaceutical product. The process comprises core comprised of fluoxetine with pharmaceutically inert substance (nuclei) and the said core coated with intermediate layer/s followed by coating with enteric polymer/s. The said core is prepared by mixing of fluoxetine with pharmaceutically inert nuclei and optionally mixed with other suitable pharmaceutical excipients. The said core is then coated with intermediate layer/s followed by enteric layer.
Hence, in a preferred embodiment of the present invention, the novel enteric compositions of the present invention comprise at least one intermediate layer that separates the core comprising fluoxetine and the enteric layer. The intermediate layer is preferably composed of a substance (or a mixture of such substances) that do not react or affect the stability of the core comprising fluoxetine. Typical examples of such substances that can be used in the intermediate layer include organic or inorganic polymers, sugars and alike. In one embodiment of the invention, the intermediate layer comprises at least one substance selected
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from a group comprising of silicon dioxide, titanium dioxide, silica, talc, microcrystalline
cellule, sodium lauryl sulphate, sodium steryl fumarate, polyethylene glycol,
polyvinylpyrrolidinone, polyvinyl alcohol, hydroxypropylcellulose and
hydroxymethylcellulose. It is an advantageous feature of this invention that the intermediate layer may also contain other pharmaceutically acceptable excipient if desired. The intermediate layer may be applied to the core using any known technique. These techniques include with any limitation for example powder coating, spraying, pan coating and alike.
In one embodiment of the invention, the enteric layer is comprised of a material that is stable in acidic medium of the stomach and thereby avoids the direct interaction between the acid medium and the contents of the composition. It is preferable that the enteric coat comprises at least one enteric polymer. Preferable examples of such enteric polymers without any limitation include, polyvinyl acetyl phthalate (PVAP) and devatives thereof, vinyl copolymers, hydroxypropylmethylcellulose (HPMC), methacrylate copolymers and acrylic acid polymers and derivatives thereof and alike. Several other commercially available enteric polymers can also be used as enteric coat if desired which include without any limitation Eudragit (Rohm Pharma), Aquateric (FMC Corporation), and alike. It is an advantageous feature of the invention that the enteric layer may also contain other pharmaceutically acceptable excipient such as talc, pigments, colouring agents, flavouring agents, stabilizers, binders, lubricants and alike if desired. The enteric layer may be applied using known techniques including for example those described for intermediate layer.
The novel compositions according to the present invention may optionally contain other pharmaceutically acceptable excipient such as diluents, binders, plastifiers, fillers, surfactants, pigments, stabilizers, disintegrating agents, lubricants, wetting agents, colouring agents, flavouring agents and alike.
The novel compositions of the present invention can be provided in several forms that are suitable for oral administration. In one preferred embodiment, the composition according to the present invention is provided in a tablet form. In another preferred embodiment, such composition is in the form of micro-tablets in capsule e.g. a gelatine capsule.
The novel enteric compositions according to the present invention generally comprise a core representing about 5 to about 98% by weight based on the total weight of the composition, rest being accounted by an intermediate and the enteric layer.
The present invention further comprises a process of preparing a pharmaceutical product, or a pharmaceutical formulation, or a medicament substantially as hereinbefore described. Suitably such a process comprises providing at least one antidepressant such as
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fluoxetine in a core constituted by mixing fluoxetine with a pharmaceutical^ inert nuclei optionally with other suitable pharmaceutical excipients and granulated optionally and the said core is further coated with one or more non-acid inert pharmaceutical excipients as "intermediate layer/s" followed by coating with at least one enteric polymer. The said process yields a novel enteric pharmaceutical formulation, typically in micro-tablets or tablets or granules/pellets in capsules (to be filled in capsules) form.
The present invention will now be further illustrated with reference to the following examples, which does not limit the scope of the invention in any way. Further different strengths of the formulation may be achieved by proportionately using a dose weight scale up or scale down formula. The concentration of the excipients may also be varied or modified to achieve the desired dissolution profile by a skilled artisan.
EXAMPLES
Example 1
An enteric-composition of Fluoxetine (equivalent to 15 mg base) according to present invention was prepared as follows.
15 mg fluoxetine Base/Capsule
Amount (mg/tablet)
16.92
12
195
2.6
12
qs
6
2.6
1.2
Ingredient
Core
Fluoxetine (EQ base)
HPMC
Lactose
Hydrogenated castor oil
Crospovidone
Water
Intermediate layer Talc
Titanium dioxide
HPMC
22 3.5 4.0 qs
Enteric layer Methacrylic acid copolymer Triethylcitrate Talc Water

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Procedure:
Appropriate quantity of Hydroxypropylmethyl cellulose (HPMC) and fluoxetine hydrochloride were dissolved in water and the contents were homogenized. The homogenized suspension was then slowly sprayed onto a lactose nuclei in a fluidised bed granulator. After all the suspension was sprayed, the nuclei were dried and mixed with hydrogenated castor oil and crospovidone. The mixed contents are then made into granules. These were then coated with an intermediate layer having composition as mentioned above. Typically, the intermediate layer was prepared by dissolving HPMC in water followed by addition of talc and titanium dioxide. The resulting contents after homogenisation were sprayed onto the granules above using a suitable coating device. Finally, these coated intermediate layer were coated with the enteric layer having composition as mentioned above. The enteric layer was prepared by mixing aqueous solutions of triethyl citrate, methacrylic acid copolymer (Eudragit) and talc and sprayed on the granules already coated with intermediate layer. These granules were either filled in gelatin capsules or compressed into tablets.
Example 2
An enteric-composition comprising fluoxetine (equivalent to 90 mg base) according to present invention was prepared as follows. The composition was prepared in the form of granules filled in the gelatin capsule.
Ingredient Amount (mg/tablet)
Core
Fluoxetine (EQ base) 90
HPMCLactosePolyethylene glycol 6000Polysorbate-80CrospovidoneWater 905259.52.3101qs
Intermediate lover Talc 21.5
Titanium dioxide 9.1
HPMC 35
Water qs
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Enteric layer
CAP 54
Triethylcitrate 12.8
Talc 18.0
Water qs
Procedure: Similar as described in Example-1
In another set of examples, the compositions described in Examples 1 & 2 were compressed
into conventional tablets and then coated with the respective intermediate and enteric layers
Pharmacokinetic study:
In vivo dissolution differences between said between the aforesaid two preparations
were demonstrated in a single dose, crossover, randomized comparative pharmacokinetic
study performed in 27 healthy volunteers.
It was found that
54 % subjects achieved Tmax earlier in test product compare to reference product;
50 % of subjects have higher Cmax compare to ref product
Thus, it was found that among the test population, 31 % of subjects had earlier
Tmax and higher Cmax in test product compare to reference product thereby
demonstrating that the absorption rate of the present formulation has significantly improved
over the test product.
While the invention has been described by way of examples and in terms of the
preferred embodiments, it is to be understood that the invention is not limited to the disclosed
embodiments. On the contrary, it is intended to cover various modifications as would be
apparent to those skilled in the art. Therefore, the scope of the appended claims should be
accorded the broadest interpretation so as to encompass all such modifications.
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We claim
1. An oral pharmaceutical composition comprising: (a) a core comprising fluoxetine or its salts and the said core comprised of pharmaceutically inert nuclei and fluoxetine or its salts mixed together, (b) an intermediate layer comprising one or more polymers and (c) an enteric layer comprising one or more enteric polymers; wherein the said composition is free of alkaline reacting compounds.
2. A pharmaceutical composition as claimed in claim 1, wherein the said core comprises of fluoxetine or its salts and pharmaceutically inert nuclei are mixed together.
3. A pharmaceutical composition as claimed in claim 1 or 2, wherein the said pharmaceutically inert nuclei comprises at least one pharmaceutically acceptable excipient.
4. A pharmaceutical composition as claimed in any one of claims 1 to 3, wherein the said pharmaceutically inert nuclei is selected from a group comprising lactose, dextrose, saccharose, starch or their mixtures.
5. A pharmaceutical composition as claimed in claim 1, wherein the formulation is an oral solid dosage form
6. A pharmaceutical composition as claimed in claim 7, wherein the formulation is a capsule, tablet, granules, pill, pellets, spheroids, granules in capsule, pellets in capsule, micro-tablets in capsule or combinations thereof.
7. The pharmaceutical formulation as claimed in claim 1, wherein the tablets or comprises enteric released fluoxetine or its salts with pharmaceutically inert nuclei mixed together and coated with intermediate layer followed by coating with enteric layer.
8. The pharmaceutical formulation as claimed in claim 1, wherein the formulation is manufactured comprising the steps of: (i) mixing pharmaceutically inert nuclei with fluoxetine or its salts; (ii) optionally, granulating the product of step (i) to form a core comprising fluoxetine (iii) coating the said core with an intermediate layer comprising at least one polymer followed by (iv) coating with one or more enteric polymers.
9. The pharmaceutical formulation as claimed in claim 1, wherein the core is manufactured by spraying a solution of fluoxetine or its salts onto pharmaceutically inert nuclei, drying
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the resultant product and granulating the dried product to form the core comprising fluoxetine.
10. The pharmaceutical formulation as claimed in claim 1, wherein at least one pharmaceutically acceptable lubricant is present additionally with the said pharmaceutically inert nuclei and fluoxetine or its salts.
11. The pharmaceutical formulation as claimed in claim claim 10, wherein the said lubricant is selected from the group comprising light mineral oil, polyethylene glycol and derivatives thereof, glyceryl behenate, hydrogenated vegetable oil, sodium steryl fumarate calcium silicate and the like.
12. The pharmaceutical formulation as claimed in claim claim 1, wherein the said intermediate layer comprises at least one material selected from a group comprising of silicon dioxide, titanium dioxide, talc, sugar and derivatives thereof, polyethylene glycol and derivatives thereof, polyvinylpyrrolidone, polyvinyl alcohol and derivatives thereof, hydroxypropylcellulose, hydroxymethylcellulose, sodium lauryl sulphate, microcrystalline cellulose, colloidal silica, sodium steryl fumarate, starch and derivatives thereof and the like.
13. The pharmaceutical formulation as claimed in claim 1, wherein the said intermediate layer contains silicon dioxide.
14. The pharmaceutical formulation as claimed in claim 1, wherein the said intermediate layer contains at least one organic or inorganic polymer or a mixture thereof
15. The pharmaceutical formulation as claimed in claim 1, wherein the said enteric layer contains at least one polymer.
16. The pharmaceutical formulation of any preceding claims, wherein the said enteric layer contains at least one polymer selected from a group comprising of cellulose acetate phthalate (CAP), polyvinyl acetyl phthalate (PVAP), vinyl copolymers, acrylic acid and copolymers and derivatives thereof and the like.
17. A pharmaceutical formulation in solid dosage form wherein the resultant product is filled in capsules using suitable capsule filling machine.
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18. A process for manufacture of enteric released formulation of fluoxetine or its salts the
process comprises the steps of: (a) spraying a medium containing fluoxetine or its salts
onto the pharmaceutically inert nuclei in a fluidised bed processor followed by drying the
resultant product and lubricating the same using suitable lubricant (b) granulating the
product of step (a) to form a core containing fluoxetine or its salts (c) coating the said
core with an intermediate layer comprising at least one polymer (d) coating the resultant
product of step (c) with an enteric layer.
19. A process as described in claim 18 wherein the individual ingredients are as described
hereinbefore including those disclosed in the specification.

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Abstract
ENTERIC COATED COMPOSITION OF FLUOXETINE
The present invention relates to a pharmaceutical composition for oral administration and in particular to an enteric coated composition of fluoxetine in the form of coated granules and/or pellets.
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