Agomelatine-based in situ gels for brain targeting via the nasal route: statistical optimization, in vitro, and in vivo evaluation

Figures & data

Table 1. The sol–gel transition temperature of agomelatine loaded SLNs in situ gels prepared using 18% w/v of Pluronic F 127 and 0.2% w/v of different types of mucoadhesive polymers.

Mucoadhesive polymer	Sol–gel transition temperatures (°C)
Carbopol	22.25 ± 1.06
Chitosan	20.50 ± 0.71
Na alginate	31.50 ± 2.12
Na CMC	22.50 ± 2.12
HPMC	29.00 ± 1.41

Table 2. Experimental runs, independent variables and measured responses of the full factorial experimental design of agomelatine-loaded SLNs in situ gels.

Formula	X1: Pluronic conc.	X2: type of mucoadhesive polymer	X3: conc. of mucoadhesive polymer	Y1: gelation temp.	Y2: m (consistency index)	Y3: n (flow index)	Y4: Q 1 h	Y5: Q 8 h	Y6: Mucociliary transport time	Y7: PS
G1	16%	HPMC	0.2%	40.00 ± 1.40	1402.50	0.82	15.14 ± 0.56	56.50 ± 0.71	10.50 ± 0.71	171.25 ± 1.76
G2		Na alginate		43.00 ± 0.71	903.30	0.98	11.04 ± 0.39	62.50 ± 0.49	6.50 ± 2.10	183.00 ± 0.71
G3		HPMC	0.4%	31.00 ± 1.40	43,762.20	0.20	15.18 ± 0.67	46.30 ± 0.85	27.00 ± 1.41	175.75 ± 1.10
G4		Na alginate		42.00 ± 0.71	700.70	0.96	14.01 ± 0.31	57.75 ± 0.38	6.00 ± 1.41	191.10 ± 6.50
G5		HPMC	0.6%	27.00 ± 2.10	30,902.90	0.021	14.26 ± 0.62	54.80 ± 0.78	24.00 ± 0.71	185.50 ± 1.69
G6		Na alginate		39.00 ± 0.71	529.50	0.95	13.56 ± 0.61	69.12 ± 0.76	4.5.00 ± 0.71	183.25 ± 4.59
G7	18%	HPMC	0.2%	27.00 ± 1.41	25,703.90	0.13	16.99 ± 0.84	54.20 ± 1.06	28.00 ± 1.41	193.40 ± 4.80
G8		Na alginate		35.00 ± 2.80	1338.30	0.45	10.28 ± 0.63	59.37 ± 0.79	8.50 ± 0.71	176.40 ± 5.09
G9		HPMC	0.4%	24.00 ± 0.35	43,431.00	0.16	21.20 ± 1.18	54.40 ± 1.48	26.00 ± 1.41	189.10 ± 8.34
G10		Na alginate		33.00 ± 1.41	4532.70	0.38	12.38 ± 1.06	68.12 ± 1.32	9.00 ± 2.80	177.90 ± 1.55
G11		HPMC	0.6%	23.00 ± 2.12	46,773.50	0.16	8.94 ± 1.35	37.60 ± 1.69	28.50 ± 0.71	182.70 ± 3.25
G12		Na alginate		33.00 ± 1.40	5937.50	0.32	19.14 ± 1.62	57.12 ± 2.03	10.50 ± 2.10	179.25 ± 1.06

Figure 1. Release profiles of the full factorial design agomelatine loaded solid lipid nanoparticles in situ gel formulae (A) G1–G6) and (B) G7–G12 in phosphate buffer (pH 6.8) and at 37 °C.

Figure 2. Transmission-electron micrograph (TEM) of the optimized agomelatine loaded solid lipid nanoparticles in situ gel formula.

Figure 3. Agomelatine (A) mean plasma concentrations and (B) mean brain concentrations after administration of intranasal Gel-3, IV agomelatine solution, and oral agomelatine suspension.

Table 3. Pharmacokinetic parameters of agomelatine in both plasma and brain.

		Rabbits plasma			Rabbits brain
Parameters	Gel-3	IV	Oral	Gel-3	IV	Oral
Cmax (ng/mL)	247.00 ± 64.40	423.00 ± 47.90	20.70 ± 3.19	148.33 ± 64.36	165.60 ± 37.70	61.20 ± 12.23
Tmax (min)	7.33 ± 4.62	2.00 ± 0.00	15.67 ± 14	2.00 ± 4.61	5.00 ± 0.00	5.00 ± 0.00
AUC0– t (ng/mL min)	6677.41 ± 1996.00	17,616.00 ± 2839.00	2828.10 ± 969.00	6570.23 ± 1995.50	12,499.60 ± 4166.50	1710.12 ± 378.24
K (min^−1)	0.0041 ± 0.0004	0.0032 ± 0.0003	0.0079 ± 0.002
t 1/2 (min)	378.93 ± 365.00	216.74 ± 23.80	91.98 ± 23.80
MRT (min)	225.28 ± 227.00	173.23 ± 5.59	151.64 ± 28.00	182.70 ± 227.07	163.19 ± 6.11	8206.90 ± 5505.04
Absolute bioavailability	37.89		16.12
Relative bioavailability	234.98
Drug targeting efficiency (DTE)	141.42
Direct transport percentage (DTP)	29.29