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:


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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 l-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.
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US Patent No. 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.
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Yet in another embodiment there is provided are 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 mixed and compressed together, (b) an intermediate layer, and (c) an enteric layer; such that the Duloxetine used is substantially fre 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..
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 phannaceutically 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, 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,
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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 furnarate, 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 derivatives thereof, vinyl
copolymers, hydroxypropylmethyl cellulose (HPMC), methacrylate copolymers and acrylic
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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 anti-ulcerant 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.
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EXAMPLES Example 1
An enteric-composition of Duloxetine (equivalent to 60 mg tablet) according to present invention was prepared as follows. 60 mg Duloxetine tablet

Ingredient Core Amount (mg/tablet)
Duloxetine (EQ base) 67.55
HPMC
Lactose
Hydrogenated castor oil
Crospovidone
Water 14 205 2.6 12
qs
Intermediate lover Talc 6
Titanium dioxide 2.6
HPMC 1.2
Enteric lover ■'-
Methacrylic acid copolymer 22
Triethylcitrate 3.5
Talc 4.0
Water qs
Procedure:
Appropriate quantity of Hydroxypropylmethyl cellulose (HPMC) and Duloxetine sodium were dissolved in water and the contents were homogenized. The homogenized suspension was then slowly sprayed onto a lactose nuclei in a fiuidised 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
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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. Examples 2
An enteric-coated tablet comprising Duloxetine (equivalent to 120 mg tablet) according to present invention was prepared as follows.
Ingredient Amount (mg/tablet)
Core
Duloxetine (EQ base) 135.1
HPMC
Lactose
Polyethylene glycol 6000
Polysorbate-80
Crospovidone
Water
90
525
9.5
23
101
qs
Intermediate layer
Talc 21.5
Titanium dioxide 9.1
HPMC 35
Water qs
CAP
Triethylcitrate Talc Water
Enteric layer
54. 12.8 18.0 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.
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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 ail such modifications.
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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 and 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 5, wherein the formulation is tablet
7. The pharmaceutical formulation as claimed in claim 1, wherein the tablets 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. The 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. And subsequently converting into tablets.
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 the resultant product and granulating the dried product to form the core comprising Duloxetine.
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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 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.
17. A process for manufacture of enteric released tablet of Duloxetine or its salts the process
comprises the steps of: (a) spraying a medium containing Duloxetine 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 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 and subsequently pressing into tablets.
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18. A process as described in claim 18 wherein the individual ingredients are as described hereinbefore including those disclosed in the specification.
Dated this the 27th day of August 200
(SHALINA AHUJA) of SUBRAMANIAM, NATARAJ & ASSOCIATES ATTONRREY FOR THE APPLICANTS
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