Site specific solubility improvement using solid dispersions of HPMC-AS/HPC SSL--mixtures.
Many upcoming drug candidates are pH-dependent poorly soluble weak bases in the pH range of the gastrointestinal tract. This often leads to a high in vivo variability and bioavailability issues. Aiming to overcome these limitations, the design of solid dispersions for site specific dissolution improvement or maintenance of a potent supersaturation over the entire gastro-intestinal pH-range, is proposed to assure a reliable drug therapy. Solid dispersions containing different ratios of Dipyridamole (DPD) or Griseofulvin (GRI) and the enteric polymer hydroxypropylmethylcellulose-acetate succinate (HPMC-AS) and the water soluble low-viscosity hydroxypropylcellulose (HPC-SSL) were prepared by hot melt extrusion (HME). The solid dispersions were evaluated for their solid state, dissolution characteristics applying a three pH-step dissolution method following an acidic to neutral pH transition and stability. The use of HPMC-AS in binary mixtures with DPD and GRI facilitated increased solubility and supersaturation at pH-controlled release of the preserved amorphous state of the dispersed drug, which even inverted the pH-dependent solubility profile of the weakly basic model drug (Dipyridamole). I.e. a potent site specific delivery system was created. With ternary solid dispersions of API, HPMC-AS and HPC-SSL, tailored release profiles with superior supersaturation over the applied pH-range could be obtained. At the same time, binary and ternary mixtures showed favorable stability properties at a temperature difference between glass transition temperature and the applied storage temperature of down to 16°C.
Boehringer-Ingelheim Pharma GmbH & Company KG, Biberach an der Riss, Germany; Eberhard-Karls-Universität Tübingen, Institut für Pharmazeutische Technologie, Tübingen, Germany.
Damir Elmar
DE
Zecevic
Boehringer-Ingelheim Pharma GmbH & Company KG, Biberach an der Riss, Germany.
Robin
R
Meier
Eberhard-Karls-Universität Tübingen, Institut für Pharmazeutische Technologie, Tübingen, Germany.
Rolf
R
Daniels
Boehringer-Ingelheim Pharma GmbH & Company KG, Biberach an der Riss, Germany; Eberhard-Karls-Universität Tübingen, Institut für Pharmazeutische Technologie, Tübingen, Germany; Rheinische-Friedrich-Wilhelms Universität Bonn, Department of Pharmaceutical Technology, Bonn, Germany. Electronic address: kgwagner@uni-bonn.de.
Karl-Gerhard
KG
Wagner
D002482:Cellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004176:Dipyridamole / Q000737:chemistry*; D004337:Drug Carriers; D004355:Drug Stability; D006118:Griseofulvin / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D044366:Transition Temperature; D014783:Viscosity
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006118:Griseofulvin; D004176:Dipyridamole; C048331:hydroxypropylmethylcellulose acetate succinate; D002482:Cellulose; D008747:Methylcellulose; C008079:hydroxypropylcellulose
Dipyridamole; Glass transition; Griseofulvin; HPC-SSL; HPMC-AS; Hot melt extrusion; Solid dispersion; Stability; Weak base