Evaluation of release techniques for nanocarriers on the basis of IVIVC-PBPK modeling
Fabian Jung (1), Lisa Nothnagel (1), Fiona Gao (2), Matthias G. Wacker (1)
Institution: (1) Fraunhofer IME Project Group Translational Medicine and Pharmacology TMP, (2) Institute of Pharmaceutical Technology Goethe University
Introduction: The drug release kinetics is one of the significant factors influencing the efficacy of nanocarriers. Often the in vitro release studies are exploited to estimate formulation characteristics, mechanism of drug release, in vivo release etc. [1]. However, not much attention has been devoted to assess favorability of different in vitro release techniques for studying release from specific nanocarriers. In current study, we have attempted to determine the most appropriate in vitro release test to assess selected nanocarriers containing hydrophobic drug for an accurate indication of an in vivo drug release.
Objectives: Aim of the current work was to compare two methods for testing the drug release from nanoparticles (viz. dialysis using dispersion releaser (DR) technique and filtration). For this purpose we have employed physiologically based pharmacokinetic (PBPK) model by studying the effect of in vitro parameters on the in silico profile. As a model formulation, flurbiprofen-loaded poly (?-caprolactone) (PCL) nanocarriers was chosen [2].
Methods: The DR technique utilizes a device fitted on USP II, which separates free drug molecules from nanoparticles by accelerated dialysis whereas the filtration method utilizes filtration through a filter membrane. The two biorelevant in vitro drug release methods were compared based on their respective release profiles as well as impact on the in silico simulations. During release testing, biorelevant media were used to simulate the human gastric and intestinal conditions. The observed in vitro release profiles were fitted in the RPT model [3]. The resulting in vitro parameters (m and b value) and permeability data from literature [4] were used to simulate absorption of the drug. The PK parameters which are required for monomolecular drug distribution and elimination were extracted from literature [5]. The model consisting of 9 compartments, which was equipped to calculate the drug flux, was developed using Stella Architect® .To validate the model, simulated profile of a marketed flurbiprofen tablet (100mg, Mylan) was compared with its observed in vivo profile [6, 7]. Additionally, the simulated and observed non-compartment PK parameters were compared by applying bioequivalence criteria. To predict the PK of PCL nanocarriers, the results of both techniques were evaluated using the PBPK model. Further, a partial sensitivity analysis was conducted by varying the release rate (±10%).
Results: In in vitro studies, both methods led to a substantial drug release i.e. 91.0 ± 5.3 % for filtration and 100.9 ± 4.1 % for the DR technique respectively. During validation, the PBPK model was able to reflect the in vivo situation when compared with mean profile and bioequivalence criteria. Although with the in silico model, both techniques produced similar results, the release data obtained with the DR technique revealed higher sensitivity in vitro and in the simulated profiles as compared to filtration technique.
Conclusions: In summary, the filtration technique enables a rapid testing with suitable simulations in the early stages of research whereas the DR based simulations detected changes in the release rate more efficiently throughout the process. Therefore based on our results the DR technique proved to be more appropriate in formulation development and quality control as compared to the filtration technique. Furthermore PBPK modeling demonstrates itself as a useful tool to estimate the influence of minor changes in in vitro results on the actual in vivo performance.
References:
[1] Shen, J., Burgess, D.J., In vitro-in vivo correlation for complex non-oral drug products: Where do we stand?. J Control Release (2013)
[2]Fabian Jung and Lisa Nothnagel et al., A comparison of two biorelevant in vitro drug release methods based on advanced physiologically-based pharmacokinetic modelling, Eur J Pharm Biopharm (in revision)
[3] G. Mohammadi et al, Reciprocal powered time model for release kinetic analysis of ibuprofen solid dispersions in oleaster powder, microcrystalline cellulose and crospovidone, J Pharm Pharm Sci, 13 (2010) 152-161.
[4] A. Avdeef, Permeability—PAMPA, in: Absorption and Drug Development: Solubility, Permeability, and Charge State, John Wiley & Sons, Inc., Hoboken, New Jersey, 2012, pp. 319-484.
[5] L.P. Volak et al., Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers, Br J Clin Pharmacol, 75 (2013) 450-462.
[6] A. Suri, B.L. Grundy, H. Derendorf, Pharmacokinetics and pharmacodynamics of enantiomers of ibuprofen and flurbiprofen after oral administration, Int J Clin Pharmacol Ther, 35 (1997) 1-8. [7] U.S.F.a.D. Administration, Ansaid® (flurbiprofen tablets, USP) 50 mg and 100 mg in, 2010.
