title: Poloxamer-based solid dispersions for oral delivery of docetaxel: Differential effects of F68 and P85 on oral docetaxel bioavailability.
abstract: Development of an oral docetaxel formulation has been hindered mainly due to its poor solubility and oral bioavailability. The aim of this study was to develop poloxamer F68/P85-based solid dispersions (SDs) for the oral delivery of docetaxel and investigate their in vivo pharmacokinetic impacts on the systemic absorption of docetaxel given orally, in comparison with a SD based on F68 alone. The F68 and/or P85-based docetaxel SDs were prepared with varying the contents of poloxamers and then evaluated in terms of morphology, crystallinity, solubility, dissolution, permeation across rat intestinal segments, and oral pharmacokinetics in rats. As a result, the SDs successfully changed the crystalline properties of docetaxel and enhanced the drug solubility and dissolution. The SD prepared with F68 alone significantly enhanced the dissolution but not intestinal permeation of docetaxel, leading to only limited enhancement of oral bioavailability (1.39-fold increase). Notably, however, the F68/P85-based SD significantly enhanced both the dissolution and intestinal permeation of docetaxel, achieving a markedly improved oral bioavailability (2.97-fold increase). Therefore, the present results suggest that the intestinal permeation factor should be taken into account when designing SD formulations for the oral delivery of BCS class IV drugs including docetaxel, and that P85 could serve as a potential formulation excipient for enhancing the intestinal permeation of docetaxel.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; Institute of Nanoscience and Technology, Hanyang University, Seoul 04763, Republic of Korea.
authors.forename: Chung Kil
authors.initials: CK
authors.lastname: Song
authors.affiliation: College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, 1666 Youngsan-ro, Muan-gun, Jeonnam 58554, Republic of Korea. Electronic address: isyoon@mokpo.ac.kr.
authors.forename: In-Soo
authors.initials: IS
authors.lastname: Yoon
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: ddkim@snu.ac.kr.
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003460:Crystallization; D000077143:Docetaxel; D065546:Drug Liberation; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D011060:Poloxalene / Q000008:administration & dosage* / Q000737:chemistry*; D020442:Poloxamer / Q000008:administration & dosage* / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D043823:Taxoids; C422648:pluronic block copolymer p85; D020442:Poloxamer; D000077143:Docetaxel; D011060:Poloxalene
keywords: Docetaxel; Freeze-drying method; Lutrol F68; Oral bioavailability; Pluronic P85; Solid dispersion