TECHNICAL FIELD OF THE INVENTION
The present invention relates to enteric multiple unit formulation comprising duloxetine and process of preparation thereof.
BACKGROUND
Duloxetine, (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine is a dual serotonin and norepinephrine reuptake inhibitor and has particular therapeutic utility as an anti-depressant.
Duloxetine is acid labile, and acid hydrolysis of its ether linkage results in a thienyl alcohol and 1-naphthol. 50% of a dosage is hydrolyzed to 1-naphthol within one hour at pH of 1.0, which is achieved under fasting conditions. At a pH of 2.0, 10% of the dosage degrades to 1-Naphthol in one hour and at a pH of 4.0, 10% degradation would take up to 63 hours.
Typically such acid sensitive compounds have been formulated as enteric-coated pellets to protect them from degradation. Enteric pharmaceutical formulations are manufactured in such a way that the product passes unchanged through the stomach of the patient, and dissolves and releases the active ingredient quickly when it leaves the stomach and enters the small intestine. Such formulations have long been used, and conventionally are in tablet or pellet form, where the active ingredient is in the inner part of the tablet or pellet and is enclosed in a film or envelope, the "enteric coating", which is insoluble in acid environments, such as the stomach, but is soluble in near-neutral environments such as the small intestine.
US patent application US 20060165776 filed by Wockhardt, discloses oral pharmaceutical compositions comprising a core of pharmaceutically inert nuclei and duloxetine, mixed and compressed together. The compressed material is further layered with an intermediate and an enteric layer comprising acrylic acid polymer.
From a technology standpoint, there are many important formulation and process parameters that must be controlled in order to obtain pellet-containing tablets and mini-tablets which ideally have the same drug release properties as the individual coated pellets. The compaction of multiparticulates into tablets or min-tablets could result in the
fusion of the multiparticulates to form a matrix tablet. Ideally, the compacted pellets should disintegrate rapidly into the individual pellets in the gastrointestinal fluids. The pellets should not fuse into a non-disintegrating matrix during compaction. The concentration of plasticizer in the coating must also be sufficient such that the polymeric coating is sufficiently elastic to maintain its integrity during the compaction process.
The amount of plasticizer in the drug coated inert nuclei of the 776 application is around 1%, which is insufficient to overcome the disadvantages of compression, and hence may result in forming a matrix tablet. There is substantial risk of segregation leading to weight variation and content uniformity problems, due to particle size differences because of compression. In addition compression leads to problems associated with a tablet sitting in the stomach until the digestion of food opens the pyloric sphincter and the tablet passes into the duodenum.
These disadvantages can be overcome by the use of multiple unit systems, wherein each individual unit is formulated with modified release characteristics. The final dosage form comprises a multiplicity of individual units contained in a formulation in such a form that individual units will be made available from the formulation in the gastrointestinal tract.
Multiple unit dosage forms possess large surface area, which promotes complete and uniform absorption, minimize peak plasma fluctuations and thus reduce the potential for systemic side effects. A further advantage of these dosage forms is that high local concentrations of the active substance in the gastrointestinal system is avoided, due to the units being distributed freely throughout the tract.
US. Pat. No. 5,508,276 assigned to Eli Lilly discloses duloxetine, in the form of enteric pellets of which the enteric layer comprises neutralized hydroxypropylmethylcellulose acetate succinate (HPMCAS).
The '276 patent also discloses that early dosage form and clinical development of duloxetine showed that it is advisable to formulate it in an enteric form, due to the stability characteristics of duloxetine in acidic solutions, that a pellet formulation was more desirable than a tablet, based on bioavailability studies which showed more
consistent plasma profiles were obtained after pellet administration, and that certain difficulties arose in preparing conventional enteric formulations.
However, according to a research article "Characterization of impurities formed by interaction of duloxetine HCI with enteric polymers hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate" published in the Journal of Pharmaceutical Sciences, duloxetine has been found to react with polymer degradation products or residual free acids present in the enteric polymers hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and hydroxypropyl methyl cellulose phthalate (HPMCP) in dosage formulations to form succinamide and phthalamide impurities respectively. The rate of formation of these impurities is accelerated by heat and humidity. Because the enteric polymers are physically separated from duloxetine by a sub-coating, the formation of these impurities indicate the migration of either duloxetine or the phthaloyl or succinyl moieties through the subcoating to enable physical contact and reaction.
Further, enteric-coated solid dosage forms described in the '276 patent are prepared by the use of a coating solution. One of the problems in the use of an aqueous coating solution of HPMCAS is that the polymer should be neutralized by the addition of certain kinds of additives and therefore requires additional processes which is time consuming and expensive.
In light of the above background, it will be appreciated by those versed in the pharmaceutical dispensing art that a need exists for an enteric multiple unit formulation of duloxetine providing complete and uniform absorption and capable of being formulated by employing a simple process that involves fewer steps.
SUMMARY In one general aspect there is provided an enteric multiple unit formulation comprising:
a) a core comprising duloxetine and one or more pharmaceutical^ acceptable excipients; and
b) an enteric layer comprising hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50 in a ratio of about 1:5 to about 5:1.
The enteric layer comprising hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50 in a ratio of about 1:5 to about 5:1 provides complete and uniform drug absorption and does not require neutralization of the polymers. More preferably, the enteric layer comprises the polymer combination in a ratio of about 1:3 to about 3:1.
In another embodiment there is provided an enteric multiple unit formulation comprising:
a) a core comprising duloxetine and one or more pharmaceutical^ acceptable excipients; and
b) an enteric layer comprising hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50 in a ratio of about 1:3 to about 3:1.
The core unit comprises water-soluble, water-insoluble or water-swellable material. Examples comprise sugar, a non-pareil seed, microcrystalline cellulose, celphere, sand silicon dioxide, glass, plastic, polystyrene, hydroxypropyl methylcellulose or mixtures thereof. The core may comprise about 15 to about 80% by weight of the formulation.
Duloxetine may be coated on the inert core to yield a final drug concentration of about 2 to about 30% by weight of the formulation. The amount of duloxetine depends on the desired dose of the drug and the quantity of multiple units, which it is desired to administer. The dose of duloxetine is in the range of 10-120 mg, more usually 20-80
mg.
In another aspect the enteric multiple unit formulation includes an intermediate layer between the core and the enteric layer.
The intermediate layer may comprise a sugar and a filler material. Sugar is added to the intermediate layer to increase the resistance of the multiple units to acid conditions. The filler material in the intermediate layer increases the smoothness and solidity of the
layer.
In another aspect there is provided a process for preparing an enteric multiple unit formulation comprising the steps of:
a) providing a core comprising duloxetine and one or more pharmaceutically acceptable excipients;
b) optionally, applying to the core an intermediate layer comprising one or more pharmaceutically acceptable excipients;
c) applying an enteric layer comprising hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50 in a ratio of about 1:5 to about 5:1;
d) filling the blend of step (c) into capsules.
In another aspect the enteric multiple unit formulation may further include a finishing layer over the enteric layer.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
DESCRIPTION The enteric multiple unit formulation of the present invention comprises a core comprising duloxetine and an enteric layer comprising hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50.
Duloxetine used herein should be understood as the base or any of its pharmaceutically acceptable salt thereof. Particularly, the salt is hydrochloride.
The core may comprise one or more of water-soluble, water-insoluble or water-swellable material. Examples comprise one or more of sugar, non-pareils, microcrystalline cellulose, celphere, sand, silicon dioxide, glass, plastic, polystyrene, ethyl cellulose or hydroxypropyl methylcellulose. The sugar may include one or more of glucose, mannitol, lactose, xylitol, dextrose, and sucrose. The core may comprise about 15 to about 80% by weight of the formulation.
According to the invention, an active core may be formed on an inert core, such as nonpareils, by applying an active coating comprising duloxetine. Duloxetine may be mixed with one or more pharmaceutically acceptable excipients, such as plasticizers, wetting agents, binders, diluents, lubricants, glidants, etc., prior to forming the active coating on
the inert core. In addition, duloxetine may be applied with a polymer to form a polymer
film.
Examples of hydrophilic polymers include but are not limited to starch, gums, alginates, polysaccharides, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, gelatin, polyvinyl alcohol, cellulose derivatives or mixtures thereof.
Cellulose derivatives comprise hydroxypropyl cellulose, hydroxypropyl methylcellulose,
hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose,
methylcellulose, sodium carboxy methylcellulose or mixtures thereof.
The hydrophilic polymer may comprise about 1 to about 20% by weight of the
formulation.
The inert core particles may be coated with the active substance dispersed in the hydrophilic polymers by a powder layering technique, wherein the active substance is applied to the core in dry form as powder. The polymer is sprayed onto the mixture of cores and active substance as a solution in such a way that solvent is evaporated, and the polymer is applied to the cores together with the active substance whereby forming a homogenous dispersion. Alternatively, the active substance may be dispersed/dissolved in polymeric solution and coated directly onto the cores.
The solvents used for making a solution, dispersion, or suspension may include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof. In general, the solvent should adequately dissolve, disperse, or suspend the active ingredient and hydrophilic polymers used.
The coating may be done using a conventional coating pan, a spray coater, a rotating perforated pan, an automated system, such as a centrifugal fluidizing (CF) granulator, a fluidized bed process, or any other suitably automated coating equipment.
Duloxetine may be coated on the inert core to yield a final drug concentration of about 2 to about 30% of the product, in general. The amount of duloxetine depends on the desired dose of the drug and the quantity of multiple units, which it is desired to
administer. The dose of duloxetine is in the range of 10-120 mg, more usually 20-80
mg.
The core may also be prepared by mixing duloxetine with one or more pharmaceutically acceptable excipients, moistening the mixture with water or a solvent, drying, and breaking the mixture into sized particles in the same size range as described above for the inert beads. This can be accomplished via the process of extrusion and
marumerization.
The enteric multiple unit formulation may optionally contain an intermediate layer. The optional intermediate layer separates the core comprising duloxetine or its pharmaceutically acceptable derivative thereof and the enteric layer. The intermediate layer between the duloxetine-containing core and the enteric layer is not required, but is a preferred feature of the formulation. The functions of the intermediate layer, if required, are to provide a smooth base for the application of the enteric layer, to prolong the enteric multiple units resistance to acid conditions, to improve stability by inhibiting any interaction between the drug and the enteric polymer in the enteric layer, and to improve stability by protecting the drug from light exposure.
The intermediate layer may comprise a sugar and a filler material.
Sugar is added to the intermediate layer to increase the resistance of the multiple units to acid conditions. The sugar in the intermediate layer may comprise about 2 to about 10% by weight of the formulation.
The filler material in the intermediate layer increases the smoothness and solidity of the layer. Examples of fillers include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch, starch pregelatinized or mixtures thereof. Fillers may comprise about 2 to about 20% by weight of the formulation.
The intermediate layer may also comprise one or more hydrophilic polymers known in the art. The hydrophilic polymer may comprise about 1 to about 20% by weight of the
formulation.
The optional intermediate layer may additionally comprise one or more pharmaceutically acceptable excipients selected from one or more of plasticizers, wetting agents, binders, diluents, lubricants and glidants and may be applied using any known technique as has been described in the preparation of a duloxetine layer. The intermediate layer may comprise about 5 to about 30% by weight of the formulation.
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 formulation. The enteric layer comprising a combination of hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50 provides complete and uniform absorption and does not require the polymers to be neutralised. It is postulated that the enteric coating prevents the migration of the drug through the formulation thereby minimizing the formation of impurities.
Preferably, hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50 are present in a ratio of about 1:5 to about 5:1 and more preferably in a ratio of about 1:3 to about 3:1.
The enteric containing coat may additionally comprise one or more pharmaceutically acceptable excipients selected from one or more of plasticizers, wetting agents, binders, diluents, lubricants, glidants, colorants and flavoring agents as mentioned earlier in the core and intermediate layers. The enteric coat may be applied using any known technique as has been described in the preparation of a duloxetine layer.
Examples of plasticizers include, but are not limited to, propylene glycol, triethylene glycol, oleic acid, ethyleneglycol monoleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebaccate, acetyl triethylcitrate, castor oil or mixtures
thereof.
Examples of wetting agents include, but are not limited to, gelatin, casein, lecithin (phosphatides), glycerol monostearate, cetostearyl alcohol, cetomacrogol, emulsifying wax, polyethylene glycols, polyoxyethylene stearates, sodium dodecylsulfate, partial fatty acid esters of polyhydroxy ethylene sorbitan, such as, polyethylene glycol sorbitan monolaurate, monopalmitate, monostearate and monooleate; polyethylene glycol sorbitan tristearate and trioleate; polyethylene glycol sorbitan monolaurate and monostearate; polyethylene glycol sorbitan monooleate, polyhydroxyethylene fatty alcohol ethers; polyoxyethylene fatty acid esters; ethylene oxide/propylene oxide block copolymers; sugar ethers and sugar esters; phospholipids and their derivatives; ethoxylated triglycerides, such as, the derivatives of castor oil (available under the trade name Cremophor) or mixtures thereof.
Examples of binders include, but are not limited to, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol or mixtures thereof.
Examples of diluents include, but are not limited to, lactose, starch, sugar alcohols, sucrose, calcium carbonate, dicalcium phosphate or mixtures thereof.
Examples of lubricants and glidants include, but are not limited to, glyceryl palmitostearate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax or mixtures thereof.
The coloring agents of the present invention may be selected from any FDA approved colors for oral use.
Suitable flavoring agents include synthetic and natural flavors such as spearmint, peppermint, lemon, orange, grape, lime, grapefruit, apple, cherry, pineapple, cocoa and
chocolate.
The enteric coating may be applied in any suitable manner known in the art, such as, for example, by using a Wurster coater. When applied, the enteric coating may be in
the form of an aqueous dispersion in water or other dispersing medium, or in the form
of a solution.
The enteric dosage forms may further comprise an optional finishing layer comprising one or more pharmaceutically acceptable excipients selected from one or more of plasticizers, wetting agents, binders, diluents, lubricants, glidants, colorants and flavoring agents and may be applied using any known technique as has been described in the preparation of a duloxetine layer.
Use of an enteric multiple unit formulation of duloxetine in the treatment of depression and other related psychotropic disorders.
The enteric multiple unit formulation of duloxetine may also be administered in combination with other anti-depressants.
The following example illustrates various aspects of the present invention. This example is for illustration only and should not be construed as limiting the scope of the
invention.

EXAMPLE Duloxetine enteric multiple unit formulation

(Example Formulation Removed)

Process:
Duloxetine hydrochloride enteric multiple units
A. Drug layer
1. Solution of Hydroxypropylmethylcellulose was prepared in purified water.
2. Duloxetine Hydrochloride was dispersed in the above solution.
3. Dispersion of step A (2) was sprayed onto non-pareil seeds.
B. Intermediate layer
1 Hydroxypropylmethylcellulose and sucrose were dissolved in purified water.
2. Talc was added to solution of step B (1) to obtain dispersion.
3. Duloxetine hydrochloride multiple units of step A (3) were coated using the dispersion of step B (2).
C. Enteric layer
1. Diethyl phthalate was dispersed in a mixture of acetone and water.
2. Hydroxypropylmethylcellulose phthalate 50 and 55 were dissolved in dispersion of step C (1).
3. Talc was added to the dispersion of step C (2).
4 Sub coated Duloxetine hydrochloride multiple units of step B (3) were coated using the dispersion of step C (3).
D. Finishing layer
1. Hydroxypropylmethylcellulose, titanium dioxide and talc were dispersed in
purified water. 2 Duloxetine hydrochloride pellets of step C (4) were coated using the dispersion
of step D (1).
The Duloxetine hydrochloride enteric multiple unit formulation prepared by the above process was filled into capsules.
Table 1: Drug Release of duloxetine enteric multiple unit formulation prepared as per Example and comparative marketed delayed release formulation CYMBALTA® (Eli Lilly) in Phosphate buffer pH 5.6, 900 ml, USP II at 50 rpm.
(Table Removed)

WE CLAIM:
1. An enteric multiple unit formulation comprising:
a) a core comprising duloxetine and one or more pharmaceutically acceptable excipients; and
b) an enteric layer comprising hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50 in a ratio of about 1:5 to about 5:1.

2. The formulation of claim 1 wherein hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50 are present in a ratio of about 1:3 to about 3:1.
3. The formulation of claim 1, wherein the core comprises an inert bead on which duloxetine is deposited as a layer comprising in addition a pharmaceutically acceptable excipient.
4. The formulation of claims 1 and 3 wherein the core comprises about 15 to about 80% by weight of the formulation.
5. The formulation of claim 3 wherein duloxetine deposited on the inert bead is about 2 to about 30% by weight of the formulation.
6. The formulation of claim 1 wherein an intermediate layer is present between the core and the enteric layer.
7. The formulation of claim 1 wherein a finishing layer is present over the enteric layer.
8. The formulation according to claim 1, wherein the formulation further comprises pharmaceutically acceptable excipients selected from one or more of plasticizers, binders, solubilizers, diluents, lubricants, glidants, colorants and flavoring agents.
9. A process for preparing an enteric multiple unit formulation according to claim 1 comprising the steps of:
a) providing a core comprising duloxetine and one or more pharmaceutically acceptable excipients;
b) optionally, applying to the core an intermediate layer comprising one or more pharmaceutically acceptable excipients;
c) applying an enteric layer comprising hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50 in a ratio of about 1:5 to about 5:1;
e) filling the blend of step (c) into capsules.
10 An enteric multiple unit formulation of duloxetine and process of preparation thereof substantially as described herein.