Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method

Eur J Pharm Biopharm. 2015 Aug;94:135-40. doi: 10.1016/j.ejpb.2015.05.010. Epub 2015 May 21.


The oral bioavailability of Sirolimus is limited by poor dissolution of the compound in the gastrointestinal tract resulting in a low bioavailability and large inter-individual differences in blood levels. Several different formulation approaches were applied to overcome these disadvantageous pharmacokinetic properties including the marketed oral solution and a tablet form containing wet milled nanocrystals. These approaches deliver improved pharmacokinetics, yet, they share the characteristics of complex production method and composition. We have developed a nanostructured Sirolimus formulation prepared by the controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. We have shown that contrary to the batch production the process could be easily intensified and scaled up; apparently the uniformity of the precipitation is heavily dependent on the production parameters, most likely the mixing of the solvent and antisolvent. We compared the physicochemical and pharmacokinetic properties of the nanostructured formula with the marketed nanoformula. We found that our method produces particles in the size range of less than 100nm. The solid form redispersed instantaneously in water and in biorelevant media. Both the solid form and the redispersed colloid solution showed excellent stability even in accelerated test conditions. The oral administration of the nanostructured formula resulted in faster absorption, higher exposure and higher trough concentrations when compared to the marked form. These advantageous properties could allow the development of solid oral Sirolimus formulae with lower strength and gel based topical delivery systems.

Keywords: Continuous flow precipitation; Enhanced bioavailability; Sirolimus.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Chemical Precipitation
  • Chemistry, Pharmaceutical
  • Colloids
  • Dosage Forms
  • Excipients / chemistry
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / pharmacokinetics*
  • Male
  • Models, Biological
  • Nanoparticles
  • Nanotechnology
  • Rats, Wistar
  • Sirolimus / administration & dosage
  • Sirolimus / blood
  • Sirolimus / chemistry
  • Sirolimus / pharmacokinetics*
  • Solubility
  • Solvents / chemistry
  • Technology, Pharmaceutical / methods*


  • Colloids
  • Dosage Forms
  • Excipients
  • Immunosuppressive Agents
  • Solvents
  • Sirolimus