Self-Microemulsifying Drug Delivery System for Improved Oral Delivery and Hypnotic Efficacy of Ferulic Acid

Figures & data

Figure 1 Excipients screen and formula optimization of SMEDDS for FA. Chemical structure of FA (A). Solubility of FA in the tested excipients (B). Compatibility analysis of formula by pseudo-ternary phase diagram in the blank (C) and drug loading conditions (D).

Table 1 BBD Assays and Verification Tests for FA-SMEDDS (n = 4)

	Contents of Evaluation	Formula 1	Formula 2
Formula ratio	Oil phase:surfactant:co-surfactant	0.1: 0.3: 0.5	0.2:0.45:0.3
	Self-emulsifying time (min)	>5 min	<30 s
SMEDDS feature	Self-emulsifying rate (%)	99.6%	99.7%
	Droplet size (nm)	16.20 ± 0.53	15.79 ± 0.60
	Polydispersity index (PDI)	0.304 ± 0.082	0.236 ± 0.039
Saturated drug loading	Verified values (g/g matrix)	0.189 ± 0.018	0.148 ± 0.006
	Predicted values (g/g matrix)	0.190	0.141
	Relative error (%)	−0.104	0.589

Figure 2 Characterization of SMEDDS. FA-SMEDDS showed small droplet size, good stability, and promoted release trait. Morphological feature (× 30,000; (A) and size distribution of FA microemulsion (B). Stability of FA microemulsion evaluated by storing in ambient conditions for 30 days: changes of appearance vs time at 25°C (C) and 37 °C (D). In vitro profiles of FA-SMEDDS and FA in dissolution media, including pH1.2 (E), pH6.8 (F), and water (G). *P < 0.05; **P < 0.01, vs FA-control group, Independent samples t-test.

Table 2 Main Pharmacokinetic Parameters of FA After Oral Administration in Rats (n=6)

	FA	FA-SMEDDS
AUC0-t (h·μg/mL)	82.86 ± 26.59	143.48 ± 39.75**
Cmax (μg/mL)	73.20 ± 14.22	83.45 ± 26.67
Tmax (h)	0.58 ± 0.20	0.61 ± 0.33
T1/2 (h)	1.39 ± 0.36	2.10 ± 0.76*
MRT0-t (h)	1.40 ± 0.34	1.84 ± 0.38**
V/F (× 10^6 L/kg)	1.22 ± 0.58	3.14 ± 1.10**
CL/F (× 10^5 L/h/kg)	2.50 ± 0.86	1.42 ± 0.31**
Fr (%)	—	185.96 ± 74.44

Notes: Results suggest that SMEDDS improved the oral bioavailability of FA by slowing its elimination. *P < 0.05; **P < 0.01, vs FA group.

Abbreviations: AUC, Area under the concentration–time curve; C_max, Peak concentration; T_max, Time to the C_max; T_1/2, Biological half-life; MRT, Mean residence time; Vz/F, Apparent volume of distribution/bioavailability; CL/F, Clearance/bioavailability; Fr, Relative bioavailability.

Figure 3 Pharmacokinetics and tissue distribution of FA after oral administration in rats. Results suggested that SMEDDS increases plasma exposure of FA, and decreases its renal distribution and enhances its brain accumulation. Plasma concentration–time profiles of FA (A). Concentration–time profiles of FA in the tissues, including heart (B), liver (C), spleen (D), lung (E), kidney (F), and brain (G).

Table 3 Analysis of Distributed Tendency of FA in the Tissues. (n=6)

	FA		FA-SMEDDS		RE (-folds)
	AUC0-t (h·μg/mL)	DP (%)	AUC0-t (h·μg/mL)	DP (%)
Heart	34.48 ± 4.36	4.6 ± 0.8	54.33 ± 27.87	5.5 ± 2.7	1.20 ± 0.59
Liver	71.24 ± 16.61	9.3 ± 1.6	123.94 ± 25.40**	12.9 ± 3.2*	1.39 ± 0.35
Spleen	13.21 ± 4.53	1.8 ± 0.8	34.54 ± 13.32*	3.6 ± 1.5*	1.98 ± 0.81
Lung	57.41 ± 11.65	7.6 ± 1.7	77.69 ± 20.34	8.2 ± 2.8	1.08 ± 0.37
Kidney	583.68 ± 97.91	76.1 ± 3.4	585.86 ± 134.70	59.4 ± 7.7**	0.78 ± 0.10
Brain	4.70 ± 1.83	0.7 ± 0.4	99.76 ± 14.04**	10.4 ± 2.3**	14.87 ± 3.34
Total	764.72 ± 104.04	100	976.12 ± 104.47	100	—

Notes: These results indicate that SMEDD change the distribution tendency of FA. *P < 0.05; **P < 0.01, vs FA group.

Abbreviations: AUC, Area under the concentration–time curve; DP, Distribution percentage; RE, Relative intake efficiency.

Figure 4 Tissue distribution of FAS and FAG after oral administration in rats. These results indicate that SMEDDS decreases the FA transformed into FAS and FAG in the kidney. Distribution of FAS in the liver (A) and kidney (B). Distribution of FAG in the liver (C) and kidney (D). AUC_0-t values of FAS (E) and FAG (F). *P < 0.05; **P < 0.01, vs FA group, Independent samples t-test.

Figure 5 Hypnotic efficacy of FA-SMEDDS in PCPA-induced insomnia mice. Findings implied that SMEDDS improved hypnotic efficacy of FA may by regulating serotonergic system. Sleep time and sleep latency (A). The levels of 5-HT (B) and 5-HIAA (C) in the hippocampus and hypothalamus. *P < 0.05; **P < 0.01, vs NC; ^†P < 0.05; ^††P < 0.01, vs MC; ^‡P < 0.05, vs DZP; ^#P < 0.05, vs FA, One-way ANOVA.

Figure 6 Possible mechanism underlining the improved effect of SMEDDS on the oral delivery and hypnotic efficacy of FA.