title: Enteric protection of naproxen in a fixed-dose combination product produced by hot-melt co-extrusion.
abstract: In this study hot-melt co-extrusion is used as processing technique to manufacture a fixed-dose combination product providing enteric protection to naproxen incorporated in the core and immediate release to esomeprazole magnesium embedded in the coat. The plasticizing effect of naproxen and triethyl citrate (TEC) was tested on the enteric polymers investigated (Eudragit(®) L100-55, HPMC-AS-LF and HPMCP-HP-50). Core matrix formulations containing HPMC-AS-LF, TEC and a naproxen load of 15, 30 and 50% were processed and characterized. The in vitro naproxen release in 0.1N HCl was prevented for 2h for all formulations. The physicochemical state of the drug in the extrudates was determined and a stability study was performed. Intermolecular interactions between naproxen and polymer were identified using attenuated total reflection Fourier-transform infrared (ATR FT-IR) spectroscopy. When esomeprazole magnesium was formulated in a polyethylene oxide 100K:polyethylene glycol 4K (1:1) matrix, separated from the naproxen-containing layer, the formulation could be easily processed and complete in vitro drug release was observed after 45 min. When co-extruding the core/coat dosage form it was observed that a third layer of polymer, separating the naproxen loaded enteric formulation in the core from the coat, is required to prevent degradation of the acid-labile esomeprazole magnesium at the core/coat interface.
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
authors.forename: A-K
authors.initials: AK
authors.lastname: Vynckier
authors.affiliation: Separation Science Group, Department of Organic Chemistry, Ghent University, Ghent, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: De Beer
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Monteyne
authors.affiliation: CONEXUS Pharma, Ghent, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Voorspoels
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: De Beer
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
authors.forename: J P
authors.initials: JP
authors.lastname: Remon
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium. Electronic address: Chris.Vervaet@UGent.be.
authors.forename: C
authors.initials: C
authors.lastname: Vervaet
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D002951:Citrates; D004338:Drug Combinations; D004339:Drug Compounding; D004355:Drug Stability; D064098:Esomeprazole / Q000737:chemistry; D009288:Naproxen / Q000008:administration & dosage* / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D013608:Tablets, Enteric-Coated
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002951:Citrates; D004338:Drug Combinations; D013608:Tablets, Enteric-Coated; D009288:Naproxen; C023001:ethyl citrate; D064098:Esomeprazole
keywords: Continuous production; Enteric protection; EsomeprazoleMg (PubChem CID: 130564); Fixed-dose combination product; Hot-melt co-extrusion; Matrix formulation; Naproxen (PubChem CID: 156391)