MULTIPLE UNIT FORMULATIONS OF DULOXETINE (18-Aug-2009)

MULTIPLE UNIT FORMULATIONS OF DULOXETINE

Mona Dhaliwal, Prakash A Jadhav, Girish Karanth, and Romi Barat Singh

Ranbaxy Laboratories Limited, Plot No 20, Sector18, Udyog Vihar, Gurgaon - 122001

Abstract

The present disclosure relates to an enteric multiple unit formulation having a core comprising duloxetine and an enteric layer comprising hydroxypropyl methylcellulose phthalate 55 and hydroxypropyl methylcellulose phthalate 50.

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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 unstable in acidic conditions, the ether linkage hydrolyzing in acid to thienyl alcohol and 1-naphthol. 50% of the dosage is hydrolyzed to 1-naphthol within one hour at pH of 1.0, whereas the degradation at a pH of 2.0 is 10%. At a pH of 4.0, 10% degradation would take up to 63 hours.

Conventionally such acid sensitive compounds have been formulated as enteric-coated compositions to protect them from degradation.

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. 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. Enteric coated matrix tablets however may have many disadvantages that 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.

U.S.

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). Enteric coated pellets showed more consistent plasma profiles were obtained after pellet administration.

However, according to a research article  “Characterization of impurities formed by interaction of duloxetine HCl 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 methy...