De Spiegeleer, Bart

Detroyer, Sven

Taevernier, Lien

Veryser, Lieselotte

English

Ghent University Academic Bibliography

                 QUALITY-BY-DESIGN RISK ASSESSMENT OF TOPICAL FORMULATION VARIABILITY   Lien Taevernier, Sven Detroyer, Lieselotte Veryser and Bart De Spiegeleer*   Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.   * Corresponding author: bart.despiegeleer@ugent.be (O. Ref.: 2015-189b) DruQuaR 1. GC-FID • Five different batches of a fusafungine market preparation • Determination of EtOH and IPM concentration  2. Franz Diffusion Cell (FDC) • Buccal pig mucosa • Dose solutions: 1 mg/mL enniatins mix in different EtOH:IPM mixtures  1:99, 3:97, 5:95 and 10:90 EtOH:IPM (V/V) Taevernier L, Veryser L, Roche N, Peremans K, Burvenich C, Delesalle C, De Spiegleer B, Human skin penetration of emerging mycotoxins (beauvericin and enniatins), Journal Of Exposure Science And Environmental Epidemiology, 2015, doi:10.1038/jes.2015.10. Taevernier L, Veryser L, Vandercruyssen K, D’Hondt M, Vansteelandt S, De Saeger S, De Spiegeleer B, UHPLC-MS/MS method for the determination of the cyclic depsipeptide mycotoxins beauvericin and enniatins in in-vitro transdermal experiments, Journal of Pharmaceutical and Biomedical Analysis, 2014, 100:50-5, doi:10.1016/j.jpba.2014.07.021. Taevernier L, Detroyer S, Veryser L, De Spiegeleer B, Enniatin-containing solutions for oromucosal use: quality-by-design ex-vivo transmucosal risk assessment of composition variability, International Journal of Pharmaceutics, 2015, doi: 10.1016/j.ijpharm.2015.06.029. 1. Determination of EtOH and IPM content • EtOH: 1.67 ± 0.03% (mean ± SEM, n =5) • IPM: 91.60 ± 2.02% (mean ± SEM, n =5) • No statistical significant difference between batches (p > 0.10)  2. Transmucosal kinetics • Enniatins able to permeate buccal mucosa! • Example enniatin B (most abundant):             • No statistical significant difference between dose solutions (p > 0.05) • Inverse relationship between log P versus kp,v, tlag and Q8h  • Local mucosa concentrations up to 33 μM (total enniatins)         marketed preparations  x 10 dosage = 330 μM  • Enniatins in topical medicines are capable of permeating the mucosa barrier! • QbD approach  no risk of a significantly different systemic enniatin availability in terms of composition variability. • Worst-case scenario  question use of enniatins in topical treatment of innocent upper respiratory tract infections  long-term chronic effects? Drug Quality & Registration (DruQuaR) format man06.001.003-v02 INTRODUCTION and OBJECTIVES  EXPERIMENTAL  RESULTS and DISCUSSION  CONCLUSIONS REFERENCES Enniatin R1 R2 R3 Enniatin A III III III Enniatin A1 III I III Enniatin B I I I Enniatin B1 I III I Enniatin C II II II Enniatin D I I II Enniatin E1 I II III Enniatin E2 I III II Enniatin F II III III FUSAFUNGINE • Mixture of cyclic hexadepsipeptide enniatins • Produced by fungi, i.a. Alternaria and Fusarium • Marketed as oral/nasal sprays, patented in 1953 • Topical treatment of upper respiratory tract infections • Claimed anti-inflammatory and bacteriostatic effects • SmPC indicates no systemic absorption 1. Do enniatins permeate mucosa and reach blood circulation? 2. Influence of excipient variability on mucosal permeation?  Quantify transmucosal kinetics MUCOSA ? • Enniatins have been shown to permeate human skin • Generally mucosal permeation > skin permeation • Formulated in ethanol (EtOH) and isopropyl myristate (IPM) 3. UHPLC-MS/MS (MRM) Analysis of the FDC samples   4. Calculations • Transmucosal kinetics • Steady-state plasma concentrations Donor chamber Buccal pig mucosa Sampling port Stir bar Receptor chamber EtOH:IPM (V/V) 1:99 3:97 5:95 10:90 1:99 3:97 5:95 10:90 2° parameters Jss (ng/(cm²×h)) Q8h (%) ENN B 20.11 ± 2.00 15.16 ± 1.98 21.24 ± 1.76 19.43 ± 2.13 0.048 ± 0.006 0.035 ± 0.005 0.053 ± 0.005 0.053 ± 0.007 ENN B1 5.54 ± 0.79 3.45 ± 0.62 5.96 ± 0.73 5.36 ± 0.93 0.018 ± 0.003 0.014 ± 0.002 0.020 ± 0.003 0.021 ± 0.004 ENN A1 0.68 ± 0.12 0.56 ± 0.16 0.90 ± 0.19 0.81 ± 0.12 0.006 ± 0.001 0.006 ± 0.002 0.008 ± 0.002 0.008 ± 0.001 ENN D 1.13 ± 0.14 6.79 ± 0.12 1.18 ± 0.10 1.16 ± 0.16 0.034 ± 0.005 0.024 ± 0.004 0.033 ± 0.004 0.038 ± 0.006 ENN E 0.22 ± 0.04 0.14 ± 0.02 0.24 ± 0.04 0.22 ± 0.04 0.014 ± 0.003 0.011± 0.002 0.015 ± 0.003 0.014 ± 0.002 1° parameters kp,v (× 10-5 cm/h) Lag time (h) ENN B 4.36 ± 0.43 3.25 ± 0.43 4.75 ± 0.40 4.68 ± 0.51 1.24 ± 0.22 1.56 ± 0.16 0.93 ± 0.20 0.94 ± 0.19 ENN B1 1.62 ± 0.23 1.06 ± 0.19 1.79 ± 0.22 1.87 ± 0.32 1.16 ± 0.24 0.73 ± 0.21 1.13 ± 0.05 0.93 ± 0.08 ENN A1 0.50 ± 0.08 0.43 ± 0.12 0.67 ± 0.14 0.70 ± 0.11 0.67 ± 0.38 n.d. 0.53 ± 0.20 0.68 ± 0.21 ENN D 3.04 ± 0.39 2.14 ± 0.33 2.95 ± 0.25 3.47 ± 0.48 1.20 ± 0.14 1.31 ± 0.09 0.94 ± 0.18 1.16 ± 0.13 ENN E 1.20 ± 0.22 0.80 ± 0.14 1.36 ± 0.21 1.45 ± 0.30 0.86 ± 0.12 0.50 ± 0.11 0.92 ± 0.05 0.86 ± 0.12 3. Clinical interpretation • Neglecting in-vivo saliva flow, GI absorption, metabolisation • Steady-state plasma concentrations     Cpl,ss,buccal = (A × kp,v × Cv)/Cl     Cl = plasma clearance    kp,v = transmucosal permeability coefficient    Cv = enniatin concentration in vehicle    A = exposed mucosal area  • Ranging from 0.026 mg/L for ENN E to 1.339 mg/L for ENN B      x 10 dosage = up to 13.4 mg/L for ENN B alone 0204060801001200 2 4 6 8Cumulative amount ENN B (ng) Time (h) 1% EtOH 3% EtOH 5% EtOH 10% EtOH

Quality-by-design risk assessment of topical formulation variability

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Quality-by-design risk assessment of topical formulation variability

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