title: Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel.
abstract: Previously, it was shown in Phase I clinical trials that solubility-limited oral absorption of docetaxel and paclitaxel can be drastically improved with a freeze dried solid dispersion (fdSD). These formulations, however, are unfavorable for further clinical research because of limitations in amorphicity of SD and scalability of the production process. To resolve this, a spray drying method for an SD (spSD) containing docetaxel or paclitaxel and subsequently drug products were developed. Highest saturation solubility (Smax), precipitation onset time (Tprecip), amorphicity, purity, residual solvents, yield/efficiency and powder flow of spSDs were studied. Drug products were monitored for purity/content and dissolution during 24 months at +15-25°C. Docetaxel spSD Smax was equal to that of fdSD but Tprecip was 3 times longer. Paclitaxel spSD Smax was 30% increased but Tprecip was equal to fdSD. spSDs were fully amorphous, >99% pure, <5% residual solvents, mean batch yield was 100g and 84%. spSDs had poor powder flow characteristics, which could not be resolved by changing settings, but by using 75% lactose as diluent. The drug product was a tablet with docetaxel or paclitaxel spSD and was stable for at least 24 months. Spray drying is feasible for the production of SD of docetaxel or paclitaxel for upcoming clinical trials.
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital/MC Slotervaart, Amsterdam, The Netherlands. Electronic address: emilia.sawicki@gmail.com.
authors.forename: Emilia
authors.initials: E
authors.lastname: Sawicki
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital/MC Slotervaart, Amsterdam, The Netherlands; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital/MC Slotervaart, Amsterdam, The Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Nuijen
mesh_terms: D000077143:Docetaxel; D004339:Drug Compounding / Q000379:methods*; D065546:Drug Liberation; D004355:Drug Stability; D000431:Ethanol / Q000032:analysis; D017239:Paclitaxel / Q000737:chemistry / Q000493:pharmacokinetics*; D011208:Powders / Q000737:chemistry*; D012995:Solubility; D013607:Tablets / Q000737:chemistry*; D043823:Taxoids / Q000737:chemistry / Q000493:pharmacokinetics*; D014867:Water / Q000032:analysis; D020002:tert-Butyl Alcohol / Q000032:analysis
chemical_list: D011208:Powders; D013607:Tablets; D043823:Taxoids; D014867:Water; D000077143:Docetaxel; D000431:Ethanol; D020002:tert-Butyl Alcohol; D017239:Paclitaxel
keywords: Dissolution; Docetaxel (PubChem CID: 148124); Freeze drying; Lyophilization; Paclitaxel (PubChem CID: 4666); Polyvinylpyrrolidone K30 (PubChem CID: 6917); Powder flow; Sodium dodecyl sulphate (PubChem CID: 3423265); Spray drying; Stability; Validation