Lucija Vuletić1,2, M Zahirul I Khan3,4, Drago Špoljarić5, Maja Radić6, Biserka Cetina-Čižmek7, Jelena Filipović-Grčić8. 1. Research and Development, PLIVA Croatia Ltd, Prilaz baruna Filipovića 25, 10000, Zagreb, Croatia. lucija.vuletic@pliva.com. 2. Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia. lucija.vuletic@pliva.com. 3. Research and Development, PLIVA Krakow, 80 Mogilska Str., 31-546, Krakow, Poland. 4. PharmaVision Australia, 28 Bourneville Ave, Brighton East, Melbourne, Vic., 3187, Australia. 5. Intellomics d.o.o., Trg Ivana Kukuljevića 4, Zagreb, Croatia. 6. Research and Development, PLIVA Croatia Ltd, Prilaz baruna Filipovića 25, 10000, Zagreb, Croatia. 7. Research and Development, PLIVA Croatia Ltd, Prilaz baruna Filipovića 25, 10000, Zagreb, Croatia. Biserka.Cetina-Cizmek@pliva.com. 8. Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia.
Abstract
PURPOSE: The aim of the present work was to classify metaxalone according to the Biopharmaceutics Classification System (BCS), to develop a clinically relevant dissolution method that can be used to predict the oral absorption of metaxalone and to establish an in vitro-in vivo correlation (IVIVC). METHODS: Solubility of the drug was studied in different pH media and permeability studies were performed using a Caco-2 cell model. The in vitro dissolution and in vivo disposition of metaxalone from 3 different immediate release (IR) tablet formulations were investigated using USP 2 apparatus and a single dose, four-way, crossover bioequivalence study in healthy humans along with an oral solution of the drug, respectively. An IVIVC was established by using a direct, differential based method. RESULTS: Metaxalone has been confirmed as a Class II drug according to BCS. Bioavailability studies performed in humans demonstrated that dissolution was the rate limiting step for bioavailability of the drug and one of the test products had significantly improved bioavailability compared to the marketed product Skelaxin®. An IVIVC model was developed that demonstrated an acceptable internal predictability. CONCLUSION: The IVIVC demonstrated that formulation factors play a significant role in dissolution and absorption of metaxalone. A pH 4.5 dissolution medium containing 0.5% NaCl with 0.2% SLS (USP apparatus 2 at 50 rpm) is clinically relevant to predict bioavailability of the drug and is superior to the USP method in terms of the Quality by Design (QbD) concept.
PURPOSE: The aim of the present work was to classify metaxalone according to the Biopharmaceutics Classification System (BCS), to develop a clinically relevant dissolution method that can be used to predict the oral absorption of metaxalone and to establish an in vitro-in vivo correlation (IVIVC). METHODS: Solubility of the drug was studied in different pH media and permeability studies were performed using a Caco-2 cell model. The in vitro dissolution and in vivo disposition of metaxalone from 3 different immediate release (IR) tablet formulations were investigated using USP 2 apparatus and a single dose, four-way, crossover bioequivalence study in healthy humans along with an oral solution of the drug, respectively. An IVIVC was established by using a direct, differential based method. RESULTS:Metaxalone has been confirmed as a Class II drug according to BCS. Bioavailability studies performed in humans demonstrated that dissolution was the rate limiting step for bioavailability of the drug and one of the test products had significantly improved bioavailability compared to the marketed product Skelaxin®. An IVIVC model was developed that demonstrated an acceptable internal predictability. CONCLUSION: The IVIVC demonstrated that formulation factors play a significant role in dissolution and absorption of metaxalone. A pH 4.5 dissolution medium containing 0.5% NaCl with 0.2% SLS (USP apparatus 2 at 50 rpm) is clinically relevant to predict bioavailability of the drug and is superior to the USP method in terms of the Quality by Design (QbD) concept.
Entities:
Keywords:
Caco-2 cell absorption; clinically relevant dissolution method; direct differential equation based in vitro-in vivo correlation; metaxalone; solubility
Authors: Paul A Dickinson; Wang Wang Lee; Paul W Stott; Andy I Townsend; John P Smart; Parviz Ghahramani; Tracey Hammett; Linda Billett; Sheena Behn; Ryan C Gibb; Bertil Abrahamsson Journal: AAPS J Date: 2008-08-07 Impact factor: 4.009
Authors: J P Skelley; G L Amidon; W H Barr; L Z Benet; J E Carter; J R Robinson; V P Shah; A Yacobi Journal: J Pharm Sci Date: 1990-09 Impact factor: 3.534