Quality improvement of melt extruded laminar systems using mixture design.
This study investigates the application of melt extrusion for the development of an oral retard formulation with a precise drug release over time. Since adjusting the formulation appears to be of the utmost importance in achieving the desired drug release patterns, different formulations of laminar extrudates were prepared according to the principles of Experimental Design, using a design for mixtures to assess the influence of formulation composition on the in vitro drug release from the extrudates after 1h and after 8h. The effect of each component on the two response variables was also studied. Ternary mixtures of theophylline (model drug), monohydrate lactose and microcrystalline wax (as thermoplastic binder) were extruded in a lab scale vertical ram extruder in absence of solvents at a temperature below the melting point of the binder (so that the crystalline state of the drug could be maintained), through a rectangular die to obtain suitable laminar systems. Thanks to the desirability approach and a reliability study for ensuring the quality of the formulation, a very restricted optimal zone was defined within the experimental domain. Among the mixture components, the variation of microcrystalline wax content played the most significant role in overall influence on the in vitro drug release. The formulation theophylline:lactose:wax, 57:14:29 (by weight), selected based on the desirability zone, was subsequently used for in vivo studies. The plasma profile, obtained after oral administration of the laminar extruded system in hard gelatine capsules, revealed the typical trend of an oral retard formulation. The application of the mixture experimental design associated to a desirability function permitted to optimize the extruded system and to determine the composition space that ensures final product quality.
Department of Chemical and Pharmaceutical Sciences, P.le Europa 1, I-34127 Trieste, Italy.
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Hasa
Department of Chemical and Pharmaceutical Sciences, P.le Europa 1, I-34127 Trieste, Italy.
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Perissutti
Department of Economics, Business, Mathematics and Statistics, P.le Europa 1, I-34127 Trieste, Italy.
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Campisi
Department of Engineering and Architecture, Via A. Valerio 6/A, I-34127 Trieste, Italy.
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Grassi
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, SI-1000 Ljubljana, Slovenia.
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Grabnar
Department of Chemical and Pharmaceutical Sciences, P.le Europa 1, I-34127 Trieste, Italy.
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Golob
Department of Chemical and Pharmaceutical Sciences, P.le Europa 1, I-34127 Trieste, Italy.
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Mian
Department of Chemical and Pharmaceutical Sciences, P.le Europa 1, I-34127 Trieste, Italy.
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Voinovich
D000284:Administration, Oral; D000328:Adult; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics; D065546:Drug Liberation; D006801:Humans; D007785:Lactose / Q000737:chemistry; D008875:Middle Aged; D008954:Models, Biological; D058996:Quality Improvement; D013678:Technology, Pharmaceutical / Q000379:methods*; D013806:Theophylline / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D014885:Waxes / Q000737:chemistry
D003692:Delayed-Action Preparations; D014885:Waxes; D013806:Theophylline; D007785:Lactose
Desirability function; In vivo studies; Laminar extrudates; Mixture experimental design; Sustained release