title: Optimized formulation of solid self-microemulsifying sirolimus delivery systems.
abstract: BACKGROUND
  The aim of this study was to develop an optimized solid self-microemulsifying drug delivery system (SMEDDS) formulation for sirolimus to enhance its solubility, stability, and bioavailability.
  
  
  METHODS
  Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase-separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed.
  
  
  RESULTS
  In the results of the oil and cosolvent screening studies, Capryol™ Propylene glycol monocapry late (PGMC) and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (Capryol™ PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio) formulation with a mean droplet size of 108.2 ± 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of sirolimus from the SMEDDS formulation were significantly higher than the raw sirolimus powder. In addition, the solid SMEDDS formulation was in a more stable state than liquid SMEDDS in pH 1.2 simulated gastric fluids. The results of the pharmacokinetic study indicate that the SMEDDS formulation shows significantly greater bioavailability than the raw sirolimus powder or commercial product (Rapamune® oral solution).
  
  
  CONCLUSIONS
  The results of this study suggest the potential use of a solid SMEDDS formulation for the delivery of poorly water-soluble drugs, such as sirolimus, through oral administration.
authors: Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.
authors: Wonkyung
authors: W
authors: Cho
authors: Min-Soo
authors: MS
authors: Kim
authors: Jeong-Soo
authors: JS
authors: Kim
authors: Junsung
authors: J
authors: Park
authors: Hee Jun
authors: HJ
authors: Park
authors: Kwang-Ho
authors: KH
authors: Cha
authors: Jeong-Sook
authors: JS
authors: Park
authors: Sung-Joo
authors: SJ
authors: Hwang
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D004355:Drug Stability; D004655:Emulsions / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D005750:Gastric Juice; D006863:Hydrogen-Ion Concentration; D008297:Male; D008954:Models, Biological; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009821:Oils / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D004655:Emulsions; D009821:Oils; D013501:Surface-Active Agents; D011092:Polyethylene Glycols; D020123:Sirolimus; C018557:glycofurol
keywords: bioavailability; microemulsion; self-emulsifying drug delivery systems; sirolimus; solubility; stability
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