The use of experimental design in the optimization of risperidone biodegradable nanoparticles: in vitro and in vivo study

Figures & data

Table 1. Independent and dependent variables in Box–Behnken design

	Levels
Independent variables	−1	0	+1
X1: Weight % of polymer to RIS (%)	50	62.5	75
X2: PLGA in PCL (%)	10	20	30
X3: PVA concentration (%)	1	2	3
	Constraints
Dependent variables	Low	High	Goal
Y1: Mean particle size (nm)	201	1358	Minimize
Y2: Encapsulation efficiency (%)	59.02	83.3	Maximize
Y3: Diffusion within 24 h (%)	12.26	82.47	Maximize

Table 2. Composition of the suggested NPs formulations according to BBD

No.	Weight % of polymer to RIS (%)	PLGA concentration (%)	Emulsifier concentration (%)	Particle size (nm)	EE (%)	Diffusion (%)
1	62.5	10	1	1358	80.3	44.25
2	75	20	3	1300	78.29	19.93
3	50	30	2	330	75.73	39.94
4	75	20	1	803	60.91	12.26
5	62.5	30	1	957	61.82	27.89
6	50	20	1	657	63.83	48.75
7	75	30	2	570	61.14	16.25
8	62.5	10	3	812	76.35	76.85
9	62.5	30	3	691	83.3	37.8
10	50	20	3	285	72.72	81.3
11	50	10	2	201	59.02	82.47
12	75	10	2	597	62.95	26.2
13	62.5	20	2	460	68.84	42.17
14	62.5	20	2	495	65.08	46.75
15	62.5	20	2	530	64.44	41.33

SD values for particle size, EE %, and diffusion within 24 h did not exceed 5%.

Figure 1. Schematic presentation for the preparation of NPs by the emulsion–solvent evaporation method.

Table 3. Estimated effects of the studied factors and associated P values for the obtained responses (Y₁–Y₃)

	Y1		Y2		Y3
Factors	Factor effect	P values	Factor effect	P values	Factor effect	P values
X1	449.25	0.0236*	−2.0025	0.5736	−44.455	0.0001*
X2	−105.0	0.4863	3.0925	0.3954	−26.9725	0.0001*
X3	−171.75	0.2738	8.7	0.0474*	20.6825	0.0004*
	−263.75	0.2560	−5.665	0.2998	−8.33917	0.0667
X1 X2	−78.0	0.7094	−9.26	0.1063	16.29	0.0051*
X1 X3	434.5	0.0793	4.245	0.4084	−12.44	0.0151*
	122.75	0.5767	2.845	0.5866	3.93583	0.3204
X2 X3	140.0	0.5104	17.215	0.0146*	−11.345	0.0213*
	796.25	0.0118*	11.3	0.0692	2.62583	0.4950

*Significant effect of factors on individual responses.

Figure 2. Standardized Pareto charts for Y1, Y2, and Y3.

Figure 3. 3D-response surface plots showing the effect of X1, X2, and X3 on the responsesY1, Y2, and Y3.

Table 4. Correlation coefficient (r) of different kinetic models and drug release mechanism (n), of RIS NPs formulations prepared according to Box Behnken design

	r			n
Formula No.	Zero order	First order	Higuchi	Korsmeyer
F1	0.794218	−0.82253	0.9042	0.5178324
F2	0.859734	−0.87377	0.945307	0.52601646
F3	0.833863	−0.85867	0.930502	0.569219
F4	0.890274	−0.8969	0.96569	0.62244066
F5	0.829114	−0.84011	0.920764	0.53678241
F6	0.815906	−0.86173	0.914214	0.5171877
F7	0.904542	−0.91286	0.971308	0.6544993
F8	0.84673	−0.9206	0.938653	0.54266162
F9	0.885838	−0.90708	0.961115	0.62065338
F10	0.862919	−0.94582	0.947685	0.53308396
F11	0.819426	−0.89499	0.918813	0.61235131
F12	0.767811	−0.78286	0.884055	0.52631624
F13	0.885615	−0.9141	0.963334	0.59659598
F14	0.872352	−0.89539	0.94842	0.61889306
F15	0.824993	−0.84916	0.924334	0.51593614
Optimized formula	0.831893	−0.88057	0.9299	0.54083131

Note: Bold numbers indicate best fit r values for the investigated kinetic models.

Figure 4. SEM image of optimized RIS NPs formula.

Figure 5. Mean plasma concentration-time profile of RIS after oral administration of single dose (0.3 mg/kg) of the marketed risperidon tablet and optimized RIS NPs, each point represents the mean of n = 6 ± SD.

Table 5. Pharmacokinetic parameters of RIS following the administration of a single oral dose (0.3 mg/kg) of the marketed tablets, and the optimized formula of RIS NPs

Pharmacokinetic parameters	Marketed tablet (risperidal®)	Optimized RIS NPs
Cmax (ng/ml)	654.66* ± 60.32	474.77 ± 21.42
tmax(hr)	2.67 ± 1.44	6.07* ± 1.16
AUC(0–24) (ng.h/ml)	5471.01 ± 1173.8	7386.09 ± 487.69
AUC(0–∞) (ng.h/ml)	5560.15 ± 1220.9	10822.71* ± 1738.01
MRT (h)	6.4956 ± 0.46	20.93* ± 4.76

Data represent the mean values of n = 6 ± SD.

*Significant at P < 0.05.