Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D

Figures & data

Table 1 Compositions of blank SNEDDS formulations varying in oil content

Formulation	F1	F2	F3	F4	F5	F6
Solutol SH15 + propylene glycol (g)	22	21	20	19	18	17
Oleic acid (g)	3	4	5	6	7	8
Oil content (%)	12	16	20	24	28	32

Abbreviation: SNEDDS, self-nanoemulsifying drug delivery system.

Table 2 Solubility results of cyclovirobuxine D in various excipients (mean ± SD; n=3)

Oil phase	Solubility (mg/g)	Surfactants and cosurfactants	Solubility (mg/g)
Maisine 35-1	65.64±4.09	Labrafac CM10	3.15±0.48
Oleic acid	124.32±8.53	Tween-80	7.86±0.57
Castor oil	73.38±4.04	Solutol SH15	7.18±0.64
Ethyl oleate	40.16±3.38	Glycerin	5.87±0.45
Isopropyl myristate	64.65±2.52	Ethanol	3.84±0.29
		Propylene glycol	9.57±1.38

Table 3 Emulsification efficacy of various surfactants

Oil	Surfactant	Number of flask inversions	Transmittance (%)	Visual observation
Oleic acid	Labrafac CM10	13	82.4	Difficult to disperse
Oleic acid	Solutol SH15	9	96.8	Spontaneous dispersion
Oleic acid	Tween-80	15	77.5	Difficult to disperse

Table 4 Emulsification abilities of various cosurfactants

Oil	Surfactant	Cosurfactant	Number of flask inversions	Transmittance (%)	Visual observation
Oleic acid	Solutol SH15	Glycerin	7	93.5	Spontaneous dispersion
Oleic acid	Solutol SH15	Ethanol	7	92.1	Spontaneous dispersion
Oleic acid	Solutol SH15	Propylene glycol	3	97.6	Spontaneous dispersion

Figure 1 Pseudo-ternary phase diagram depicting the nanoemulsion region (NE).

Notes: (A) K_m=1:2; (B) K_m=1:1; (C) K_m=2:1.
Abbreviations: S/Cos, surfactant/cosurfactant; K_m, surfactant/cosurfactant of different mass ratios.

Figure 2 Effect of oil content and cyclovirobuxine D loading on globule size.

Notes: (A) *P<0.05, **P<0.01 vs 10% oil; (B) *P<0.05, **P<0.01 vs 1% cyclovirobuxine D.

Figure 3 TEM images of the nanoemulsion in the different scale of 0.2 μm (A) and 0.05 μm (B).

Abbreviations: SNEDDS, self-nanoemulsifying drug delivery system; TEM, transmission electron microscopy.

Figure 4 In vitro release profiles of SNEDDS and market tablets.

Abbreviation: SNEDDS, self-nanoemulsifying drug delivery system.

Figure 5 Transport amount of cyclovirobuxine D in 4 hours (A) and Caco-2 cell viability after transport study (B) ^#P>0.05 vs market tablets.

Abbreviations: SNEDDS, self-nanoemulsifying drug delivery system; A–B, from apical side to basolateral side; B–A, from basolateral side to apical side.

Table 5 Pharmacokinetic parameters of cyclovirobuxine D following oral administration to rabbits (mean ± SD, n=6)

Parameters	Market tablets	SNEDDS
AUC (ng⋅h/mL)	1,408.72±49.84	2,820.52±127.06a
Tmax (h)	3.56±0.12	2.87±0.13a
Cmax (ng/mL)	108.42±3.79	224.72±9.88a
ka (h^−1)	0.373±0.02	0.459±0.02a
ke (h^−1)	0.055±0.002	0.058±0.002
t1/2 (h)	12.65±0.56	11.94±0.33

Note:

a Significant differences with parameters obtained from market tablets.

Abbreviations: AUC, area under the curve; T_max, time to reach maximum plasma concentration; C_max, maximum plasma concentration; k_e, elimination rate; k_a, absorption rate; t_1/2, elimination half-life; SNEDDS, self-nanoemulsifying drug delivery system; SD, standard deviation.

Figure 6 Plasma concentrations vs time profile after oral administration of SNEDDS and market tablets (mean ± SD, n=6).

Abbreviations: SNEDDS, self-nanoemulsifying drug delivery system; SD, standard deviation.