Pharma Ingredients & Services. Welcome to more opportunities. Custom Synthesis Excipients Active Ingredients ExActConcepts Example: Itraconazole Bioavailability enhancement of poorly soluble APIs Enhanced solubilization out of solid glassy solutions prepared by Hot-Melt Extrusion Increased solubility Sufficient bioavailability is indispensable for an active pharmaceutical ingredient s effect. Poor solubility of drug molecules is one root cause of insufficient bioavailability. By enhancing solubility, higher blood concentrations of poorly soluble drugs can be achieved respectively dosages can be reduced and the risk of severe side effects can be decreased.
Task: Enhance bioavailability of poorly soluble drugs Concept: Produce solid glassy solutions with itraconazole by hot-melt extrusion Solubilizer Soluplus an amphiphilic polymer with polyvinyl caprolactam polyvinyl acetate - polyethylene glycol graft copolymer structure, serves solubilization of drug molecules. H chemical structure of Soluplus It is a polymeric solubilizer to form stable solid glassy solutions by hot-melt extrusion. The excipient s solubilizing capability yields in an increase in solubility and thus enhances bioavailability of poorly soluble drugs. Excellent extrudability of the excipient and its capability to form solid solutions with many active ingredients, makes it very easy to work with Soluplus. N n m l H
Example formulation Example poorly soluble API: Itraconazole Composition Parameter set Manufacturing instructions Preparation of Solid Solution Ingredient Function Quantity [%] Itraconazole API 20.0 Soluplus Solubilizer 80.0 HME Equipment Screw speed Twin-screw extruder, 16 mm (Polylab, ThermoFisher) (+ 3 mm die) 200 rpm Mix itraconazole and Soluplus. Produce itraconazole-soluplus extrudates by hot-melt extrusion with equipment shown alongside. Average barrel temp. 160 C Powder feed rate 1 kg / h Mill extrudates to a size of 250 μm.
Analytical results In-vitro results DSC (Differential scanning calorimetry) DSC Q2000 V24.4 Build 116 (TA Instruments), 2 K/min Itraconazole-Soluplus extrudates Itraconazole crystalline Commercial drug product Itraconazole-Soluplus extrudate amorphous Itraconazole in the commercial product seemed mainly amorphous (clear interpretation of the DSC curves impossible due to overlaid peaks from other excipients) Dissolution profile Itraconazole crystalline Itraconazole-Soluplus extrudates Commercial drug product Crystalline itraconazole has a very low apparent solubility (5 μg/ml 0.1 N HCl) Drug release of itraconazole in the commercial product and itraconazole in the form of an extruded solid solution is significantly improved (both formulations enable supersaturated solutions) Drug release [%] USP apparatus (USP 35), 50 rpm, 700 ml HCl (0.08 N, ph 1.1, SGF (simulated gastric fluid); itraconazole measured by UV spectroscopy at 258 nm
Analytical results In-vivo results (beagle dogs) Plasma concentration vs. time profile Drug concentration [ng/ml] Itraconazole crystalline Itraconazole-Soluplus extrudates Commercial drug product Itraconazole in the commercial product and itraconazole in the form of an extruded solid solution show significantly increased bioavailability compared to crystalline itraconazole The mean plasma concentrations achieved with Soluplus were approximately twice as high as the ones obtained with a commercially available drug product Time [h] à Significantly better performance of Itraconazole-Soluplus extrudates can be explained by the capability of Soluplus to form stable solid solutions and by the formation of itraconazol loaded micells upon dissolution [1]. [1] H. Hardung et al, Combining HME & Solubilization. Soluplus The Solid Solution, Drug Delivery Technology 10, 3 (2010) Source: Bioavailability Enhancement of Itraconazole with Solid Solutions Based on Soluplus F. Guth 1, M. Becker 2, R. Buesen 2, K. Kolter 1 1 R& D Pharma Ingredients 2 Toxicology, BASF SE, 67057 Ludwigshafen, Germany I E-mail: karl.kolter@basf.com
Conclusion form the in-vitro and in-vivo data Superior performance of the Itraconazole-Soluplus extrudates (when compared to commercial Itraconazole product) is shown through the in-vivo data Consequence No solitary review of the in-vitro data and attempt to predict in-vivo data theoretically à Avoid misleading project decision based on in-vitro data by considering in-vivo data 03_120816e-00 www.innovate-excipients.basf.com solid-dispersion@basf.com Disclaimer The data contained in this publication are based on our current knowledge and experience. In view of the many factors that may affect processing and application of our product, these data do not relieve processors from carrying out their own investigations and tests; neither do these data imply any guarantee of certain properties, nor the suitability of the product for a specific purpose. Any descriptions, drawings, photographs, data, proportions, weights etc. given herein may change without prior information and do not constitute the agreed contractual quality of the product. It is the responsibility of the recipient of our products to ensure that any proprietary rights and existing laws and legislation are observed. (01 / 2012) = registered trademark of BASF SE