Research Disclosure no longer supports Internet Explorer

Method of manufacturing medicine capsules Duloxetine is a prescription medicine commonly used to treat major depression, pain, and anxiety disorders. It belongs to the class of drugs known as serotonin- norepinephrine reuptake inhibitors (SNRIs). Duloxetine is (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine, and is commonly used as its hydrochloride salt. Duloxetine Hydrochloride is manufactured in the form of 20, 30, 40 and 60, 90 and 120 mg gastro-resistant capsules. Each capsule contains enteric-coated pellets of duloxetine hydrochloride. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Some examples for the preparation of pharmaceutical compositions of duloxetine are described in EP693282B1, EP2380563B1, EP2575457B1 or EP2544667B1. A nitrosamine impurity known as N-nitroso-duloxetine (NDLX) was detected in low levels in medicines containing duloxetine. In recent years drug regulatory authorities have issued guidance to pharmaceutical manufacturers on the control of nitrosamine impurities in medicines. Nitrosamine presence in drugs can be risky for patients as these compounds are carcinogenic, even at trace levels. However, nitrosamine formation can be avoided by controlling and monitoring the nitrite concentration in pharmaceutical products and raw materials and developing processes to reduce or eliminate nitrosamine formation. The following examples show different processes to produce enteric duloxetine pellets with the level of nitrosamine impurities required by health authorities during the shelf- life of the product. The pellets comprise a) an inert bed b) a core consisting of duloxetine, a nitrite scavenger and pharmaceutically acceptable excipients; c) a separating layer comprising pharmaceutically acceptable excipients; and d) an enteric layer. Optionally the pellets may comprise one or more additional layers which may contain additional amounts of nitrite scavenger, which may be applied before or after the above layers. Examples The pelletization coating process by layering is performed in fluid bed equipment (stainless steel vessels, equipped with a stirrer and a homogenizer) where spherical particles are fluidized and a film coating (the coating fluid) is sprayed on them while they are simultaneously dried. EXAMPLE 1 Composition per g Pre-Active layer Sugar 710-850 MIC 413.43 Hypromellose 21.1 Talc 3.02 Ascorbic acid 0.88 Purified water 158.022 Duloxetine layer Duloxetine HCl 200 Hypromellose 80 Talc 65.5 Ascorbic acid 5.29 Purified water 1000 Separating layer Hypromellose 90.5 Sucrose 15.1 Talc 15.1 Ascorbic acid 3.84 Purified water 679 Enteric layer Eudragit L30-D55 220 Triethyl citrate 6.6 Titanium dioxide 7.05 Talc 6.6 Purified water 334.6 Pre-active layer A first phase (Pre-Film coating # 1), in which an adjusted pH aqueous suspension with a nitrite scavenger (Ascorbic acid), a bi...