title: High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation.
abstract: OBJECTIVE
  To design a high drug loading formulation of self-microemulsifying/micelle system.
  
  
  METHODS
  A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400).
  
  
  RESULTS
  As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400 = 8:2 was selected, and achieved the target loading level (200 mg/mL). The formulation formed fine emulsion/micelle (49.1 nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation.
  
  
  CONCLUSIONS
  The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.
authors.affiliation: Production Engineering Department (Formulation Technology), Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. sakaikni@chugai-pharm.co.jp
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sakai
authors.forename: Kouki
authors.initials: K
authors.lastname: Obata
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Takano
authors.forename: Masaki
authors.initials: M
authors.lastname: Shibata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Maeda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Mizutani
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Terada
mesh_terms: D000042:Absorption; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003459:Crystallins / Q000737:chemistry; D004285:Dogs; D004655:Emulsions / Q000737:chemistry*; D008823:Micelles; D009821:Oils / Q000737:chemistry; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D003459:Crystallins; D004655:Emulsions; D008823:Micelles; D009821:Oils; D004364:Pharmaceutical Preparations; D012997:Solvents; D013501:Surface-Active Agents; D014867:Water; D011092:Polyethylene Glycols