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 DULOXETINE"

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 invention and the manner in which it is to be performed:


BA_formul_0 12_compl
FIELD OF INVENTION
The present invention relates to a pharmaceutical composition for oral administration and in particular to an enteric coated composition of duloxetine in the form of coated granules and/or pellets. BACKGROUND OF THE INVENTION
Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Its chemical designation is (+)-(S)-N-methyl- -(l-naphthyloxy)-2-thiophenepropylamine hydrochloride. Duloxetine hydrochloride is administered orally and used to treat major depressive disorder, stress urinary incontinence and diabetic peripheral neuropathic pain. Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water and commercially available as Cymbalta and Yentreve.
Due to its chemical structure, duloxetine is prone to acid-catalyzed hydrolysis, which results in the formation of potentially harmful degradation products and a decrease in the biovailability of duloxetine. Duloxetine is unstable in solution at pH values less than 2.5, therefore it is degraded in the gastric environment of the stomach. Acid hydrolysis of its ether linkage results in thienyl alcohol and 1-naphthol. Hydrolysis is not desirable as 1-naphthol has toxic properties. Therefore, it is advisable to use enteric coated dosage forms, which pass through the stomach unchanged and do not release the active substance until they have reached the small intestine. Enteric coatings have been used for many years to arrest the release of the drug from orally ingestible dosage forms. Depending upon the composition and/or thickness, the enteric coatings are resistant to stomach acid for required periods of time before they begin to disintegrate and permit slow release of the drug in the lower part of stomach or upper part of the small intestine. A pellet form comprising duloxetine has been proposed as the most suitable form of administration for consistent plasma concentration profiles.
However, the use of gastric polymers in the enteric formulation gives rise to several problems regarding stability of duloxetine. Since conventionally used gastric coatings contain acidic functional groups, they can cause acid-catalysed degradation of duloxetine. Also, it has been shown that duloxetine reacts with some of these coatings to form amide adducts. These interactions reduce the potency of the drug and can alter the physical characteristics of the coating.
Therefore, it has been proposed that a separating or barrier layer can be used between the duloxetine-containing layer and the enteric coating to prevent the contact between the duloxetine-containing layer and the polymers in the enteric coating. This helps to achieve the desired level of stability of duloxetine in the gastric pellets.
2

BA_formul_0 12_compl
US patent 5,508.276 relates to a duloxetine enteric formulation in the form of enteric pellets wherein the enteric layer comprises hydroxypropylmethylcellulose acetate succinate (HPMCAS). The enteric duloxetine pellet comprises a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer comprising HPMCAS and a pharmaceutically acceptable excipient; d) an optional finishing layer. In a preferred embodiment, the optional separating layer comprises sucrose to improve acid resistance and stability. In US 5,508,276 it is described that duloxetine reacts with many enteric coatings to form slowly or even insoluble coating, which can lead to the decreased bioavailability of duloxetine. Based on the compatibility with duloxetine, hydroxypropylmethylcellulose acetate succinate was chosen as a enteric polymer which is compatible with the desired release of duloxetine from the pharmaceutical formulation. HPMCAS is partially neutralized with ammonium ions to the degree that from about 0% to about 25% of the succinic acid groups are neutralized.
US patent application 20060165776 relates to enteric compositions suitable for oral administration comprising duloxetine. or its pharmaceutical derivatives and methods for preparing such compositions. Such compositions contain a core consisting of a duloxetine or its pharmaceutical derivatives, the said core comprised of a pharmaceutically inert nuclei and the duloxetine or its pharmaceutical derivatives thereof compressed together, an intermediate and an enteric layer. The composition is free of alkaline reacting compounds. We herein describe an enteric coated formulation of Duloxetine 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 Duloxetine or its pharmaceutically acceptable derivative thereof. The said core comprised of pharmaceutically inert nuclei and the duloxetine 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 duloxetine or its pharmaceutically acceptable derivative thereof. Another object of the present invention is an enteric released solid pharmaceutical composition adapted for oral administration.
3

BA_formul_0 12_compl
In yet another there is provided an enteric duloxetine 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 Duloxetine or its salts, the said core comprised of pharmaceutically inert nuclei and the Duloxetine or its salts like HC1 mixed and compressed together, (b) an intermediate layer, and (c) an enteric layer; such that the duloxetine 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 duloxetine 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 duloxetine or its pharmaceutically acceptable derivative thereof and optionally one or more suitable excipients 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 duloxetine 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 duloxetine or its salts mixed and compressed together. The mixing here may be purely physical mixing, deposition,
4

BA_formul_0 12_compl
coating, adsorption, aggregation or adhesion and alike. Such a mixing of the said pharmaceutically inert nuclei and duloxetine 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 duloxetine, 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 duloxetine, 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 duloxetine 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 duloxetine 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 duloxetine 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 duloxetine 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 duloxetine. 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
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
5

BA_formul_0 12_compl
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 duloxetine in a core constituted by mixing, duloxetine with a pharmaceutically 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.
6

BA_formul_0 12_compl
EXAMPLES Example 1
An enteric-composition of Duloxetine (equivalent to 60 mg base) according to present invention was prepared as follows. 60 mg duloxetine Base/Capsule
Ingredient Amount (mg/tablet)
Core
Duloxetine (EQ base) 67.358
HPMC
Lactose
Hydrogenated castor oil Crospovidone Water 16
205
2.6
12
qs
Intermediate layer
Talc 6
Titanium dioxide 2.6
HPMC 1.2
Enteric layer
Methacrylic acid copolymer 22
Triethylcitrate 3.5
Talc 4.0
Water qs
Procedure:
Appropriate quantity of Hydroxypropylmethyl cellulose (HPMC) and duloxetine 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

BA_formul_0 12_compl
(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. Examples 2
An enteric-composition comprising duloxetine (equivalent to 120 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
Duloxetine (EQ base) 135
HPMC 90
Lactose 525.
Polyethylene glycol 6000 9.5
Polysorbate-80 2.3
Crospovidone 101
Water qs
Intermediate layer
Talc 21.5
Titanium dioxide 9.1
HPMC 35
Water qs
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
29 % subjects achieved Tmax earlier in test product compare to reference product;

BA_formul_0 12_compl
52 % 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.
9

BA_formul_0 12_compl We claim:
1. An oral pharmaceutical composition comprising: (a) a core comprising duloxetine or its salts and the said core comprised of pharmaceutically inert nuclei and duloxetine 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 duloxetine 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 duloxetine or its salts with pharmaceutically inert nuclei mixed together and coated with intermediate layer followed by coating with enteric layer.
8. he pharmaceutical formulation as claimed in claim 1, wherein the formulation is manufactured comprising the steps of: (i) mixing pharmaceutically inert nuclei with duloxetine or its salts; (ii) optionally, granulating the product of step (i) to form a core comprising duloxetine (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 duloxetine or its salts onto pharmaceutically inert nuclei, drying
fO

BA_formul_0 12_compl
the resultant product and granulating the dried product to form the core comprising duloxetine.
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 duloxetine or its salts.
11. The pharmaceutical formulation as claimed in 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 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 as claimed in any preceding claim, 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.
18. A process for manufacture of enteric released formulation of duloxetine or its salts the process comprises the steps of: (a) spraying a medium containing duloxetine or its salts
11

BAformuI 012_compl
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 duloxetine 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 claimed in in claim 18 wherein the individual ingredients are as described hereinbefore including those disclosed in the specification.
Dated this the 27th day of August 2008
(SHALINA AHUJA) of SUBRAMANIAM, NATARAJ & ASSOCIATES ATTORNEY FOR THE APPLICANT
12