FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
PHARMACEUTICAL COMPOSITIONS OF DULOXETINE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009, Gujarat,
India
The following specification describes the invention:
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TECHNICAL FIELD OF THE INVENTION
The present invention relates to solid oral pharmaceutical compositions of duloxetine, process for preparing such compositions and method of using such compositions. Preferably, the invention relates to a delayed release composition of duloxetine comprising a core comprising duloxetine, optional separating coat and an enteric coat.
BACKGROUND OF THE INVENTION
Duloxetine is a mixed serotonin and norepinephrine reuptake inhibitor having a prominent antidepressant activity (Berk et al, Int Clin Psychopharmacol, 1997 May; 12(3): 137-40). Chemically, duloxetine is designated as (+)-(S)-A/-methyl-y-(1-naphthyloxy)-2-thiophenepropylamine and is sold as its hydrochloride salt under the brand name Cymbalta® manufactured by Eli Lilly. US 4,956,388 patent discloses the synthesis of duloxetine and its potent serotonin and norepinephrine uptake inhibitory property.
US 5,508,276 patent assigned to Elli Lilly and Co. discloses that it is advisable to formulate duloxetine in an enteric form due to its instability in acidic solutions. It also teaches enteric formulation of duloxetine in the form of enteric pellets of which the enteric coat comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). The selection of HPMCAS as the polymer was arrived after finding that duloxetine reacted with many enteric coatings to form a slowly or even insoluble coating. It is disclosed that the use of a polymer other than HPMCAS formed a pellet formulation having a disadvantageous drug-release profile and low bioavailability. US 5,508,276 also describes the difficulty of preparing high-loaded enteric formulation of duloxetine which would not release duloxetine in acid environments. The marketed formulation of Cymbalta® comprises enteric pellets as taught by US 5,508,276.
Jansen et al, J Pharm Sci, 87 (1), 1998: 81-85 discloses that duloxetine reacts with degradation products or residual free acids present in the enteric polymer such as hydroxypropyl methylcellulose phthalate to form impurities such as phthalamide impurities.
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US 5,910,319 patent assigned to Eli Lilly discloses enteric fluoxetine pellet comprising a) a core consisting of fluoxetine and one or more pharmaceutically acceptable excipients; b) an optional separating layer comprising a non-deducing sugar and one or more pharmaceutically acceptable excipients; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and one or more pharmaceutically acceptable excipients; d) an optional finishing layer. The said compositions were described to provide a convenient and effective once per week dosing of higher doses of fluoxetine (e.g., 60-120 mg), having blunt initial release of fluoxetine and lesser side effects.
WO 2003/13480 filed by Dr. Reddy's Laboratories Ltd. discloses an enteric fluoxetine formulation comprising: (a) a core comprising fluoxetine or a pharmaceutically accepted salt, solvate, enantiomers or mixtures thereof including racemic mixture, in an amount of 90 mg base equivalent of fluoxetine, (a) an optional smoothening layer, (a) an enteric coating layer comprising an at least one enteric coating polymers selected from the group consisting of Eudragit L100-55, Eudragit L 100, Eudragit S 100, hydroxypropyl methylcellulose pthalate, cellulose acetate pthalate, polyvinyl acetate pthalate; an at least one plasticisers selected from the group consisting of triethyl citrate, polyethylene glycol, diethyl pthalate or dibutyl pthalate; an at least one lubricant or glidants selected from the group consisting of talc, magnesium stearate, kaolin or colloidal silicon dioxide, and (a) an optional finishing layer. The composition was described to be advantageous as it could be prepared without a separating coat. The composition was found to be therapeutically equivalent to the commercially available product Prozac® Weekly 90 mg capsule.
There is still a need in the art to prepare enteric formulations of duloxetine which gives maximum release of duloxetine from the dosage form in the intestine. It was surprisingly found that enteric formulation of duloxetine can be prepared with phthalate containing polymers in the enteric coat, without compromising on the drug-release and bioavailability. The compositions show comparable dissolution profile and are expected to be bioequivalent to that of Reference product -Cymbalta® (commercially available in US market).
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SUMMARY OF THE INVENTION
One embodiment discloses a delayed release pharmaceutical composition comprising duloxetine and at least one pharmaceutically acceptable excipient, wherein the composition comprising:
a) a core comprising duloxetine,
b) optionally a separating coat on the core, and
c) an enteric coat on the core or the separating coat;
wherein the enteric coat comprises hydroxypropyl methylcellulose phthalate (HPMCAP).
Another embodiment discloses a delayed release pharmaceutical composition comprising duloxetine and at least one pharmaceutically acceptable excipient, wherein the composition comprising:
a) a core comprising duloxetine,
b) optionally a separating coat on the core, and
c) an enteric coat on the core or the separating coat;
wherein the enteric coat comprises cellulose acetate phthalate (CAP).
Another embodiment discloses a delayed release pharmaceutical composition comprising duloxetine and at least one pharmaceutically acceptable excipient, wherein the composition comprising:
a) a core comprising duloxetine,
b) optionally a separating coat on the core, and
c) an enteric coat on the core or the separating coat;
wherein the enteric coat comprises polyvinyl acetate phthalate (PVAP).
Yet another embodiment discloses a process for preparing a delayed release pharmaceutical composition comprising duloxetine and at least one pharmaceutically acceptable excipient; wherein the process comprises:
a) preparing a core,
b) optionally coating the core with a separating coat, and
c) coating the product of step (a) or (b) with an enteric coat;
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wherein the enteric coat comprises hydroxypropyl methylcellulose phthalate (HPMCP) or cellulose acetate phthalate (CAP) or polyvinyl acetate phthalate (PVAP).
Yet another embodiment discloses a method for treatment of major depressive disorder; management of diabetic neuropathic pain associated with diabetic peripheral neuropathy; treatment of moderate to severe stress urinary incontinence in women comprising administering to a patient in need thereof a delayed release pharmaceutical composition comprising duloxetine and at least one pharmaceutically acceptable excipient, the composition comprising:
a) a core comprising duloxetine,
b) optionally a separating coat on the core, and
c) an enteric coat on the core or the separating coat;
wherein the enteric coat comprises hydroxypropyl methylcellulose phthalate (HPMCAP) or cellulose acetate phthalate (CAP) or polyvinyl acetate phthalate (PVAP).
DETAILED DESCRIPTION OF THE INVENTION
The term "delayed release pharmaceutical composition" as described herein is intended to include compositions which provide a maximum release of duloxetine in the less acidic environment of the intestine relative to the more acidic environment of the stomach.
The term "duloxetine" as described herein is intended to include duloxetine free base or pharmaceutically acceptable acid addition salts thereof, racemic mixture, individual enantiomer or mixtures thereof. The preferred salt is duloxetine hydrochloride. The particle size of duloxetine as used herein may vary from 1 |j.m to 200 μm.
The term "core" as described herein is intended to include anything below the separating coat or when the separating coat is absent, anything below the enteric coat. Thus the core may contain inert core covered with duloxetine, core containing duloxetine, or mixtures thereof. The inert core may comprise inert non-
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pareils which are conventionally used in pharmaceutical industry and are readily available. The inert non-pareils may be of any pharmaceutically acceptable excipient such as starch, sugar, micro-crystalline cellulose, vegetable gums, waxes, and the like. Preferably, the inert non-pareils are of starch and sugar. The size of the inert non-pareils may vary from 0.1 mm-2 mm. The core may also be prepared by techniques such as granulation or extrusion-spheronization. For example, the core may be prepared by mixing at least one pharmaceutically acceptable excipient and duloxetine, moistening the mixture with water or a solvent, granulating and subsequently drying to obtain granules which may be used as the core. Alternatively, such granules may be compressed into a tablet, which may be used as the core. The core may also be prepared by mixing at least one pharmaceutically acceptable excipient and duloxetine, wetting with water or organic solvent and mixing in a high shear granulator to form a homogeneous wet mass, extruding the wet mass to form extrudates which are subsequently spheronized to form spheres which may be used as the core. The core may be present in an amount ranging from 10 % to 90 % by weight of the composition.
The delayed release compositions may comprise a separating coat between the core and the enteric coat. The separating coat may provide stability by inhibiting direct contact of the components of the core and the enteric polymer in the enteric coat. The separating coat may also provide protection to the core during its passage from the stomach to the intestines. Preferably, the separating coat is compatible with duloxetine and the enteric coat and does not affect the dissolution of the composition. The separating coat may comprise at least one film forming polymer such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone; and the like. The separating coat may be prepared by dissolving an appropriate amount of film forming polymer into a suitable solvent system such as water, organic solvent such as alcohol, methylene chloride, and the like; or mixtures thereof, and spraying the solution or suspension on core using a suitable apparatus. The separating coat may be present in an amount ranging from 0.5 % to 30 % by weight of the composition.
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The "enteric coat" as described herein may comprise a suitable pH-dependent polymer selected from cellulose acetate phthalate, methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, and the like. The polymer may be used either alone or in combination with other polymers. The enteric coat may be applied by dispersing or suspending the enteric polymer in a suitable medium, such as water or aqueous acidic or alkaline solutions, or in organic solvents such as methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methylene chloride, ethylene chloride, ethyl acetate, or mixtures thereof, and the resultant solution or suspension may be sprayed directly on the core or separating coat, followed by drying to obtain delayed release composition. The enteric coat may be present in an amount ranging from 0.5 % to 30 % by weight of the composition.
The pharmaceutical compositions as described herein may additionally comprise at least one pharmaceutically acceptable excipient selected from diluent, disintegrant, binder, lubricant, glidant, plasticizer, anti-tacking agent, opacifying agent, and the like. This invention does not include compositions where enteric coat comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS).
Diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitol, sorbitol, erythritol; and mixtures thereof. Diluent may generally be added to increase the bulk volume of the powder to facilitate granulation or compression. Diluent, such as a sugar, may also be added as a component of the coat, such as in the separating coat, to impart sticking and acid-resistance properties to the coating layer. The diluent may be present in an amount ranging from 1 % to 80 % by weight of the composition.
Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline
cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof.
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The disintegrant may be present in an amount ranging from 1 % to 20 % by weight of the composition.
Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. Binder may be used as a component of the coat to ensure proper adhesion of the subsequent coats. The binder may be present in an amount ranging from 0.1 % to 25 % by weight of the composition.
Lubricant may be selected from metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof. Glidant may be selected from talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate; and mixtures thereof. The lubricant or glidant may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
Plasticizer may be used in a coat to increase the flexibility and strength of the layer and may be selected from propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate; or mixtures thereof. The plasticizer may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
Anti-tacking agent may be used in a coat to aid bulk build-up and form a smooth surface and may be selected from talc, kaolin, finely divided silicon dioxide, glyceryl monostearate, and the like. The anti-tacking agent may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
Opacifying agent may be used in a coat to prevent photo-degradation and may be selected from titanium dioxide, iron oxides, and the like. The opacifying agent
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may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
The pharmaceutical compositions as described herein may be prepared by different techniques. For example, when an inert core is used, non-pareils may be coated with a seal coat comprising a film forming polymer, e.g. ethylcellulose, and excipients like plasticizer, anti-tacking agent and opacifying agent. The components of the seal coat may be dissolved or dispersed in an appropriate solvent and the dispersion may be coated on the core in a conventional coating pan or fluidized bed equipment (such as a Wurster or Glatt) and the coated cores
may then be dried. A coat of duloxetine may then be applied to such coated cores using similar process as above, wherein duloxetine may be built up on the coated cores by spraying a suspension or dispersion comprising duloxetine and excipients such as binder, plasticizer, anti-tacking agent and opacifying agent. Alternatively, the duloxetine coat may also be applied by powder-coating, wherein the coated cores as described above are maintained in a sticky state, a mixture of duloxetine and powdered excipients such as binder, plasticizer, anti-tacking agent and opacifying agent are added continuously or periodically so as to adhere to the sticky cores. When the entire duloxetine coat has been applied, the drug coated cores are dried. The drug-coated cores may optionally be coated with a separating coat or may directly be coated with the enteric coat. The enteric coat may be applied by dispersing or suspending the enteric polymer in a suitable medium which may additionally comprise excipients such as plasticizer, anti-tacking agent and opacifying agent, and the resultant dispersion may be sprayed on the drug-coated cores, followed by drying to obtain enteric-coated pellets. The enteric pellets may be filled into capsules of suitable size or provided as any suitable composition such as tablet or sachet.
The compositions may also be prepared by providing a core prepared by techniques such as granulation. For example, pharmaceutically acceptable excipients such as diluent, disintegrant, binder, glidant, and duloxetine may be mixed; the mixture may be moistened with water or a solvent, granulated and subsequently dried to obtain granules which may be used as the core. The core may be optionally coated with a separating coat or directly coated with the enteric
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coat by processes as described herein to obtain pellets which may be filled into capsules of suitable size or provided as any suitable composition such as tablet or sachet. Alternatively, the uncoated granules may be lubricated and compressed into a tablet, which may be used as the core. The tablet may be optionally coated with a separating coat and subsequently coated with the enteric coat.
The compositions may also be prepared by providing a core prepared by techniques such as extrusion-spheronization wherein at least one pharmaceutically acceptable excipient and optionally duloxetine are mixed and wetted with water or organic solvent in a high shear granulator to form a homogeneous wet mass, the wet mass is extruded to form extrudates which are subsequently spheronized to form spheres, which may be used as the core. The core may be optionally coated with a separating coat and subsequently coated with the enteric coat by processes as described herein to obtain pellets which may be filled into capsules of suitable size or provided as any suitable composition such as tablet or sachet. Alternatively, the uncoated cores may be compressed into a tablet, which may be used as the core. The tablet may be optionally coated with a separating coat and subsequently coated with the enteric coat.
In one embodiment, delayed release duloxetine compositions may be prepared by
providing inert non-pareils;
coating the inert non-pareils with duloxetine;
coating the drug-coated cores with a separating coat;
coating the product obtained above with an enteric coat;
optionally mixing the enteric-coated pellets with at least one
pharmaceutically acceptable excipient; and
filling the enteric-coated pellets into capsules.
In another embodiment, delayed release duloxetine compositions may be prepared by
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preparing a core by mixing duloxetine and at least one pharmaceutical^ acceptable excipient selected from the group consisting of diluent, disintegrant, glidant and binder;
granulating the mixture with a solvent or a binder solution,
drying the granules;
optionally coating the granules with a separating coat;
coating the product obtained above with an enteric coat;
optionally mixing the enteric-coated granules with at least one
pharmaceutical^ acceptable excipient; and
filling the enteric-coated granules into capsules or compressing into
tablets.
In another embodiment, delayed release duloxetine compositions may be prepared by
preparing a core by mixing at least one pharmaceutically acceptable
excipient selected from the group consisting of diluent, disintegrant,
glidant and binder;
granulating the mixture with a solvent,
drying the granules;
coating the granules with duloxetine;
optionally coating the granules with a separating coat;
coating the product obtained above with an enteric coat
optionally mixing the enteric-coated granules with at least one
pharmaceutically acceptable excipient; and
filling the enteric-coated granules into capsules or compressing into
tablets.
The pharmaceutical compositions as described herein may be illustrated by the following example which is not to be construed as limiting the scope of the invention:
EXAMPLE 1: Capsules of enteric duloxetine pellets comprising Hydroxypropyl methylcellulose phthalate (HPMCP) in the enteric coat
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Sr. no Ingredients Mg /capsule
Stage 1: Seal coating
1 Non-pareils 50.00
2 Ethyl cellulose 3.00
3 Talc 0.75
Stage 1 : Drug coating
4 Duloxetine HCI 22.40
5 HPMC 2.87
6 Purified water Q.S.
Stage 1 1: Separating coat
7 HPMC 1.98
8 Purified water Q.S.
Stage IV : Enteric coating
9 HPMC phthalate 28.61
10 Diethyl phthalate 2.97
11 Talc 5.57
PROCEDURE: Ethyl cellulose and talc were dissolved in methanol and methylene chloride and sprayed on non-pareils. Duloxetine was suspended in HPMC solution and sprayed on to seal coated non-pareils. The drug-coated cores were coated with a separating coat by spraying a dispersion of hydroxypropyl methylcellulose in purified water. HPMC phthalate was dissolved in methanol and methylene chloride; and diethyl phthalate and talc were added. The solution was sprayed on to drug-coated non-pareils to obtain enteric pellets, which were filled in a capsule of suitable size.
TABLE 1: COMPARATIVE DISSOLUTION DATA OF EXAMPLE 1 AND REFERENCE PRODUCT (CYMBALTA®)

Time % Drug Release
EXAMPLE 1 REFERENCE PRODUCT
0.1 N HCI for 2 hours 0.0 0.0
15 min 49.4 51.1
30min 70.4 78.2
45 min 78.9 89.0
60 min 84.7 92.2
[Dissolution is carried out in USP apparatus Type I at 100 RPM, 37.5° C; Dissolution medium: 1000 ml 0.1 HCI (for 2 hours) followed by 6.8 phosphate buffer]
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EXAMPLE 2: Capsules of enteric duloxetine pellets comprising cellulose acetate phthalate (CAP) in the enteric coat

Sr. no Ingredients Mg /capsule
Stage 1: Seal coating
1 Non-pareils 50.00
2 Ethyl cellulose 3.00
3 Talc 0.75
Stage I : Drug coating
4 Duloxetine HCI 22.40
5 HPMC 2.87
6 Purified water Q.S.
Stage I 1: Separating coat
7 HPMC 1.98
8 Purified water Q.S.
Stage IV : Enteric coating
9 Cellulose acetate phthalate 28.61
10 Diethyl phthalate 2.97
11 Talc 5.57
PROCEDURE: Ethyl cellulose and talc were dissolved in methanol and methylene chloride and sprayed on non-pareils. Duloxetine was suspended in HPMC solution and sprayed on to seal coated non-pareils. The drug-coated cores were coated with a separating coat by spraying a dispersion of hydroxypropyl methylcellulose in purified water. Cellulose acetate phthalate was dissolved in methanol and methylene chloride; and diethyl phthalate and talc were added. The solution was sprayed on to drug-coated non-pareils to obtain enteric pellets, which were filled in a capsule of suitable size.
EXAMPLE 3: Capsules of enteric duloxetine pellets comprising polyvinyl acetate phthalate (PVAP) in the enteric coat

Sr. no Ingredients Mg /capsule
Stage I: Seal coating
1 Non-pareils 50.00
2 Ethyl cellulose 3.00
3 Talc 0.75
Stage 1 : Drug coating
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4 Duloxetine HCI 22.40
5 HPMC 2.87
6 Purified water Q.S.
Stage 1 1: Separating coat
7 HPMC 1.98
8 Purified water Q.S.
Stage IV : Enteric coating
9 Polyvinyl acetate phthalate 28.61
10 Diethyl phthalate 2.97
11 Talc 5.57
PROCEDURE: Ethyl cellulose and talc were dissolved in methanol and methylene chloride and sprayed on non-pareils. Duloxetine was suspended in HPMC solution and sprayed on to seal coated non-pareils. The drug-coated cores were coated with a separating coat by spraying a dispersion of hydroxypropyl methylcellulose in purified water. Polyvinyl acetate phthalate was dissolved in methanol and methylene chloride; and diethyl phthalate and talc were added. The solution was sprayed on to drug-coated non-pareils to obtain enteric pellets, which were filled in a capsule of suitable size.
Dated this 9th Day of March, 2007

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ABSTRACT
The present invention relates to solid oral pharmaceutical compositions of duloxetine, process for preparing such compositions and method of using such compositions. Preferably, the invention relates to a delayed release composition of duloxetine comprising a core comprising duloxetine, optional separating coat and an enteric coat.