title: Process optimization by use of design of experiments: Application for liposomalization of FK506.
abstract: Design of experiments (DoE) can accelerate the optimization of drug formulations, especially complexed formulas such as those of drugs, using delivery systems. Administration of FK506 encapsulated in liposomes (FK506 liposomes) is an effective approach to treat acute stroke in animal studies. To provide FK506 liposomes as a brain protective agent, it is necessary to manufacture these liposomes with good reproducibility. The objective of this study was to confirm the usefulness of DoE for the process-optimization study of FK506 liposomes. The Box-Behnken design was used to evaluate the effect of the process parameters on the properties of FK506 liposomes. The results of multiple regression analysis showed that there was interaction between the hydration temperature and the freeze-thaw cycle on both the particle size and encapsulation efficiency. An increase in the PBS hydration volume resulted in an increase in encapsulation efficiency. Process parameters had no effect on the ζ-potential. The multiple regression equation showed good predictability of the particle size and the encapsulation efficiency. These results indicated that manufacturing conditions must be taken into consideration to prepare liposomes with desirable properties. DoE would thus be promising approach to optimize the conditions for the manufacturing of liposomes.
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Toyota
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: oku@u-shizuoka-ken.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods*; D007166:Immunosuppressive Agents / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D016559:Tacrolimus / Q000737:chemistry*
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D007166:Immunosuppressive Agents; D008081:Liposomes; D010714:Phosphatidylethanolamines; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; D016559:Tacrolimus
keywords: Box-Behnken design; Design of experiments; Liposomes; Process optimization