FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
"STABILISED ENTERIC FORMULATION OF DULOXETINE HYDROCHLORIDE AND PROCESS FOR THEIR PREPARATION
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:
1

ABSTRACT
The technical field of present invention relates to a stable duloxetine hydrochloride composition wherein the formulation is stabilized using physical barriers of coating between the drug layer and the enteric layer. The invention provides preparation of duloxetine enteric formulation comprising a drug layer, a first layer coated on the drug layer comprising a basic material, a second layer comprising a neutral agent and a third layer, of enteric film for the composition.
The invention has been developed primarily for use as a solid oral dosage form and will be described hereinafter with reference to this application.
BACKGROUND OF THE INVENTION
Duloxetine is a Serotonin-norepinephrine reuptake inhibitor (SNRI). it is a potent dual reuptake inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE), possessing comparable affinities in binding to NE- and 5-HT transporter sites. It is a less potent inhibitor of dopamine reuptake. Its chemical designation is (+)-(5)-A^-methyl-y -(1-naphthyloxy)-2-thiophenepropylamine hydrochloride.
The commercial product CYMBALTA® by Eli Lilly and Company contains duloxetine hydrochloride.
DESCRIPTION OF THE PRIOR ART
2

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
The composition of duloxetine can be known from the prior art patents as follows: U.S. Pat. No. 5,508,276 Anderson, Neil R discloses an enteric formulation of the antidepressant drug, duloxetine, is in the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.
OBJECT OF THE INVENTION
Early dosage form and clinical data of duloxetine showed that it follows degradation in acidic solutions. Because of these reasons; when these compounds are to be formulated into a preparation for oral administration, it should be coated with an enteric coating to thereby prevent the decomposition of the same with gastric acid. It is therefore advisable to formulate duloxetine in an enteric form.
Moreover, duloxetine reacts with many enteric coatings polymers to form certain impurities and degradation products as prior literature discloses that duloxetine hydrochloride((5)-J/V-methyl-3-(l-naphthale-nyloxy)-2-thiophenepropan amine hydrochloride) has been found to react with polymer degradation products or residual free acids present in the enteric polymers hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP) in dosage
3

formulations to form succinamide and phthalamide impurities, respectively. Moreover, the rate of formation of the impurities is accelerated by heat and humidity.
However a great deal of research has been done in this area to prevent degradation of duloxetine with other pharmaceutically accepted excipients but it always results in stability problems.
In order to avoid these difficulties and to overcome the problems associated with the prior arts, the present inventors have conducted extensive studies in order to further stabilize the compound. As a result, they have found that the drug layer including a physical barrier has proved to have an advantageous drug-releasing profile in duloxetine composition.
Thus, the formation of impurities is minimized by incorporating a physical barrier separating the enteric coating from the drug. This barrier comprises of both a basic material and a neutral agent which is impermeable forming a physical barrier separating the enteric coating from the drug to prevent the migration of residual free acids or polymer degradation products present in the enteric polymers thus preventing the formation of impurities in the composition.
It is therefore an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
4

SUMMARY OF THE INVENTION
The term "stable" as used herein refers to chemical stability of duloxetine in solid dosage forms.
Suitable substances for use as the basic material of the invention may be selected from, but not restricted to, substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonate co-precipitate; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as AI2O3 6MgOCO212H2O, Mg6Al2(OH)16 CO3.4H2O , MgOAl2 O32(SiO2) nH2O or similar compounds, organic pH-buffering substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable substances. The choice and quantity of the basic material is optimized for effective pH control.
It is also understood by a person skilled in the art that a combination of one or more different basic materials may be used in a population of basic material.
The neutral agents may be low substituted hydroxypropyl cellulose, mannitol, lactose, sucrose, crospovidone etc.
5

Examples of the enteric material to be used in the present invention may include hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, methacrylic acid/methyl methacrylate copolymer and polyvinyl acetate phthalate etc.
Examples of coloring agents include any FDA approved colors for oral use.
Thus, the present invention provides an exclusive advantage over the prior art by using physical barriers of coating between the drug layer and the enteric layer hence preventing both drug-polymer reaction and generation of impurities respectively.
Dated this 20th day of July 2007

To:
The Controller of Patents, Patent Office, Mumbai 400 037