Nanoemulsions as novel oral carriers of stiripentol: insights into the protective effect and absorption enhancement

Figures & data

Figure 1 Schematic illustration of the engineering of STP-NEs: the acidolytic route of STP and approach for bioavailability enhancement via nanoemulsions.

Abbreviations: STP, stiripentol; STP-NEs, stiripentol-loaded nanoemulsions.

Figure 2 Formulation screening.

Notes: The effect of ratios of PM/MCT (A) and drug/excipients (B) on particle size of STP-NEs.

Abbreviations: PDI, polydispersity index; PM/MCT, poly(ethylene glycol) monooleate/medium-chain triglycerides; STP-NEs, stiripentol-loaded nanoemulsions.

Figure 3 Characterization of STP-NEs.

Notes: (A) size distribution, (B) appearance, and (C) morphology observed by TEM.

Abbreviations: STP-NEs, stiripentol-loaded nanoemulsions; TEM, transmission electron microscopy.

Figure 4 Acidic destabilization curves of free STP and STP-NEs in simulated gastric fluid indicated by the retained percentage of STP (n=3, mean ± SD).

Abbreviations: SD, standard deviation; STP, stiripentol; STP-NEs, stiripentol-loaded nanoemulsions.

Figure 5 The release profiles of STP from nanoemulsions performed in pH 6.8 phosphate buffer and 0.1 M HCl based on a dialysis method (n=3, mean ± SD).

Abbreviations: SD, standard deviation; STP, stiripentol; STP-NEs, stiripentol-loaded nanoemulsions.

Figure 6 The stability of STP-NEs characterized by particle size as well as polydispersity index (PDI) for a short-term investigation (30 days).

Abbreviation: STP-NEs, stiripentol-loaded nanoemulsions.

Table 1 Main pharmacokinetic parameters of STP in Sprague Dawley rats after oral administration of commercial formulation (Diacomit^®) and STP-NEs

Formulations	Diacomit^®	STP-NEs
Cmax (μg/mL)	2.02±0.47	6.16±0.53*
Tmax (h)	0.94±0.32	1.18±0.46
AUC0−t (μg/mL*h)	10.21±0.53	21.06±0.69*
T1/2 (h)	2.59±0.78	2.70±0.52
RBA (%)	N/A	206.2

Notes: Data shown as mean ± SD (n=5).

* Significantly different from the commercial formulation using ANOVA (P=0.05).

Abbreviations: AUC, area under the plasma STP concentration–time curve; C_max, maximum concentration; h, hour; RBA, relative bioavailability calculated based on AUC_0−t; SD, standard deviation; STP, stiripentol; STP-NEs, STP-loaded nanoemulsions; T_1/2, plasma half-time; N/A, not applicable; T_max, peak time.

Figure 7 The plasma STP concentration versus time profiles in rats following oral administration of commercial formulation of STP and STP-NEs (n=6, mean ± SD).

Abbreviations: SD, standard deviation; STP, stiripentol; STP-NEs, stiripentol-loaded nanoemulsions.

Table 2 The effective intestinal permeability (P_eff) of STP and STP-NEs evaluated by the in situ single-pass intestinal perfusion (n=3)

Intestinal segment	Peff
	Free STP	STP-NEs
Duodenum	2.393±0.107 E-4	1.529±0.128 E-4*
Jejunum	1.918±0.171 E-4	1.189±0.093 E-4*
Ileum	2.175±0.084 E-4	0.882±0.030 E-4*

Note: One-way ANOVA,

* significantly different from free STP (P=0.05).

Abbreviations: STP, stiripentol; STP-NEs, stiripentol-loaded nanoemulsions; ANOVA, analysis of variance.

Figure 8 The relative cell viability of Caco-2 incubated with nanoemulsions at different PM concentrations (n=3, mean ± SD).

Abbreviations: PM, poly(ethylene glycol) monooleate; SD, standard deviation.