title: A pre-formulation study of a polymeric solid dispersion of paclitaxel prepared using a quasi-emulsion solvent diffusion method to improve the oral bioavailability in rats.
abstract: OBJECTIVE
  To preliminarily develop a surfactant-free, polymeric solid dispersion (PSD) of paclitaxel suitable for oral administration.
  
  
  METHODS
  A co-solvent quench method was applied to screen the proper polymer matrix of the PSD which were prepared in a liquid system using a quasi-emulsion solvent diffusion method (QESDM). Three dissolution experiments and two in vivo tests in rats were used to explain the differences among the formulations.
  
  
  RESULTS
  The theoretical solubility ratio of amorphous/crystalline PTX was 92.6 (37 °C). Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was chosen as the polymer carrier of the PSD and a porous silicon dioxide [called white carbon black (WCB)] was selectable to be used to further adjust the dissolution rate. The absolute oral bioavailability (AOB, 20 mg/kg) of the three formulas [HPMCAS/paclitaxel/WCB = 4/1/0 (F1), 8/1/0 (F2) and 4/1/4 (F3), w/w/w] were 11.8, 13.6 and 25.6%, respectively. The AOB of F3 is nearly seven times higher than that (3.8%) of paclitaxel material (a control). The advantage of higher HPMCAS/paclitaxel ratio of F2 in a dissolution test was not reflected in the first in vivo test due to the relatively higher dose of polymer which could not be effectively dissolved under the limitation of intestinal environment. This was deduced from the dissolution tests and was finally validated when the oral dose of PTX (and thus polymer) was reduced. The relevant AOBs (10 mg/kg) were 10.4, 20.8 and 19.6%, respectively.
  
  
  CONCLUSIONS
  The PSD is a promising formulation strategy and the QESDM is a practical preparation method to implement such formulation design.
authors.affiliation: a Department of Pharmaceutics , School of Pharmaceutical Science, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Hongze
authors.initials: H
authors.lastname: Piao
authors.affiliation: a Department of Pharmaceutics , School of Pharmaceutical Science, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.affiliation: a Department of Pharmaceutics , School of Pharmaceutical Science, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Piao
authors.affiliation: a Department of Pharmaceutics , School of Pharmaceutical Science, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Peixiang
authors.initials: P
authors.lastname: Wang
authors.affiliation: a Department of Pharmaceutics , School of Pharmaceutical Science, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Shi
authors.affiliation: a Department of Pharmaceutics , School of Pharmaceutical Science, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.affiliation: a Department of Pharmaceutics , School of Pharmaceutical Science, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Fude
authors.initials: F
authors.lastname: Cui
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004058:Diffusion; D004655:Emulsions / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011108:Polymers / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D004655:Emulsions; D011108:Polymers; D012997:Solvents; D017239:Paclitaxel
keywords: Hydroxypropyl methylcellulose acetate succinate; low dose metronomic chemotherapy; oral bioavailability; paclitaxel; solid dispersion