Brain delivery of valproic acid via intranasal administration of nanostructured lipid carriers: in vivo pharmacodynamic studies using rat electroshock model

Figures & data

Table 1 Preparations, dosage, routes, and times of administration of different preparations of VPA used in the different experimental groups

Experimental group	Preparation	Administered dose (mg/kg)	Route of administration	Timea (min)
1	Controlb	–	Intranasal	15, 30, 60, 90, and 120
2	Controlb	–	IP	15, 30, 60, 90, and 120
3	NLC of VPA	4	Intranasal	15, 30, 60, 90, and 120
4	NLC of VPA	20	IP	15, 30, 60, 90, and 120
5	Sodium VPA solution	30c	Intranasal	15, 30, 60, 90, and 120
6	Sodium VPA solution	150c	IP	15, 30, 60, 90, and 120

Notes:

a Time between administration of valproate and electrical stimulation;

b Blank contains all of the components of nanoparticles except VPA;

c Dosage is equivalent to VPA.

Abbreviations: VPA, valproic acid; NLC, nanostructured lipid carrier; IP, intraperitoneal.

Table 2 Composition and physical properties of the optimized NLCs of VPA

Cetyl palmitate (%)	Poloxamer 188 (%)	Lipoid (%)	Octyldodecanol (%)	VPA (%)	Drug loading (%)	Particle size (nm)	Zeta potential (mV)	Drug release after 21 days (%)	Polydispersity index
0.8	1	0.2	0.2	0.8	47 ± 0.8	154 ± 16	−10 ± 0.5	75 ± 1.9	0.2 ± 0.1

Abbreviations: NLCs, nanostructured lipid carriers; VPA, valproic acid.

Table 3 Concentration of VPA in plasma and brain after administration of different formulations (n = 6)

Preparation	Route	Weight of rats (g) mean ± SD	Administrated dose (mg/kg)	Plasma concentration 60 min after administration (μg/mL) mean ± SD	Brain concentration 60 min after administration (μg/g) mean ± SD	Brain:plasma ratio after 60 min
Controla	Intranasal	197.3 ± 11	–	–	–	–
Controla	IP	178 ± 8	–	–	–	–
NLC of VPA	Intranasal	189 ± 20	4	7.96 ± 2.9	64.35 ± 5.7	8.4 ± 0.32
NLC of VPA	IP	181 ± 12	20	11.35 ± 5.8	19.85 ± 8.5	1.65 ± 0.09
Sodium VPA solution	Intranasal	188 ± 24	30b	3.87 ± 1.9	23.36 ± 8.3	6.77 ± 0.73
Sodium VPA solution	IP	209 ± 9	150b	275.85 ± 39.5	112 ± 16	0.42 ± 0.02

Notes:

a Control contains all of the components of nanoparticles except VPA;

b Dosage is equivalent to VPA.

Abbreviations: VPA, valproic acid; NLC, nanostructured lipid carrier; IP, intraperitoneal.

Figure 1 Comparison between the effect of sodium valproate solution positive control (30 mg/kg), NLCs of VPA (4 mg/kg), and control NLCs (without VPA) in nasal route of administration on MES seizure protection which was assessed as the decrease of extension:flexion (E:F) ratio (n = 6).

Notes: *Statistically significant difference (P < 0.05) with respect to the control (empty) NLC group according to one-way ANOVA and Tukey test; ^¥Statistically significant difference (P < 0.05) with respect to the positive control group according to 1-way ANOVA and Tukey test.

Abbreviations: E:F ratio, extension:flexion ratio; VPA, valproic acid; NLC, nanostructured lipid carrier; MES, maximal electroshock.

Figure 2 Comparison between the effect of sodium valproate solution positive control (150 mg/kg), NLCs of VPA (20 mg/kg), and control NLCs (without VPA) in IP route of administration on MES seizure protection which was assessed as the decrease of extension:flexion (E:F) ratio (n = 6).

Notes: *Statistically significant difference (P < 0.05) with respect to the control (empty) NLC group according to one-way ANOVA and Tukey test; ^¥Statistically significant difference (P < 0.05) with respect to the positive control group according to 1-way ANOVA and Tukey test.

Abbreviations: E:F ratio, extension:flexion ratio; VPA, valproic acid; NLCs, nanostructured lipid carriers; MES, maximal electroshock; IP, intraperitoneal.

Figure 3 Comparison between MES seizure protection effect of NLCs of VPA (4 mg/kg) in nasal route and sodium valproate solution (150 mg/kg) as positive control in IP route after different times of drug administration (P > 0.05) (n = 6). There is no statistical difference in any times according to independent t test.

Abbreviations: E:F ratio, extension:flexion ratio; VPA, valproic acid; NLCs, nanostructured lipid carriers; MES, maximal electroshock; IP, intraperitoneal.

Figure 4 Correlation between MES seizure protection effect and brain:plasma concentration ratio of preparations in nasal and IP route of administration.

Abbreviations: E:F ratio, extension:flexion ratio; VPA, valproic acid; NLC, nanostructured lipid carrier; MES, maximal electroshock; IP, intraperitoneal.