Optimized sildenafil citrate fast orodissolvable film: a promising formula for overcoming the barriers hindering erectile dysfunction treatment

Figures & data

Table 1. Variables and their levels in the Box–Behnken design.

	Levels
Independent variables	Low	Medium	High
X1 = Film forming polymer (HPC) %	1	2	3
X2 = Film modifier (GG) %	0.2	0.4	0.6
X3 = Plasticizer (PG) %	1	1.5	2
	Constraints
Dependent variables	Low	High	Goal
Y1 = Disintegration time (seconds)	95	230	Minimize
Y2 = In vitro dissolution (%)	16.76	79.22	Maximize

Table 2. Experimental runs and observed values of responses for BBD.

	Factors			Responses
Run	X1	X2	X3	Y1	Y2
F1	1	0.4	2	100	79.22
F2	3	0.4	2	180	28.5
F3	3	0.2	1.5	210	24.5
F4	1	0.2	1.5	150	45.32
F5	2	0.6	2	110	55.45
F6	2	0.2	1	162	41.96
F7	2	0.2	2	95	29.27
F8	1	0.6	1.5	170	61.74
F9	2	0.6	1	200	22.19
F10	3	0.4	1	165	18.18
F11	1	0.4	1	190	60.9
F12	3	0.6	1.5	230	16.76
F13	2	0.4	1.5	172	20.22
F14	2	0.4	1.5	150	22.84
F15	2	0.4	1.5	140	21.33

Figure 1. The phase solubility diagrams of sildenafil citrate with different concentrations of the three β-cyclodextrin carriers.

Table 3. Factor effects and associated p values for Y₁ and Y₂ responses.

	Response
	Y1			Y2
Factor	Factor effect	F ratio	p value	Factor effect	F ratio	p value
X1	43.75	9.94	0.025*	−39.81	147.10	0.0001*
X2	23.25	2.81	0.155	3.77	1.32	0.302
X3	−58.0	17.47	0.009*	12.30	14.05	0.013*
X1²	53.0	6.73	0.049*	25.09	26.99	0.004*
X1 X2	0.0	0.00	1.000	−12.08	6.77	0.048*
X1 X3	52.5	7.16	0.044*	−4.0	0.74	0.428
X2²	19.0	0.87	0.395	6.13	1.61	0.260
X2 X3	−11.5	0.34	0.583	22.98	24.50	0.004*
X3²	−43.5	4.54	0.087	25.37	27.58	0.003*

* Significant effect of factors on individual responses.

Table 4. Regression Equations of the fitted models.

Response	Equation
Disintegration time (Y1)
Cumulative % release (Y2)

Figure 2. (A) Response surface plot (3D) showing the effect of X₁ and X₃ on Y₁. (B) contour plot showing relationship between various levels of two variables to attain fixed values of Y₁. (C) Response surface plot (3D) showing the effect of X₁, X₂, and X₃ on Y₂. (D) Contour plot showing relationship between various levels of two variables to attain fixed values of Y₂.

Table 5. Optimum desirability with observed values of the responses for the optimized sildenafil citrate ODFs formulation.

Factor	Optimum value	Response	Predicted value	Observed value
Film forming  % (X1)	1	Disintegration time (Y1)	92.70	89.45
Film modifier  % (X2)	0.5	Cumulative % release (Y2)	83.68	86.56
Plasticizer % (X3)	2

Figure 3. Plasma concentration of Sildenafil citrate following the administration of the reference (Viagra® tablets), and optimized ODF. Data represent the mean values of n = 6 ± S.D.

Table 6. Pharmacokinetic parameters ± S.D of sildenafil following the administration of a single oral dose (50 mg) of the market formulation (Viagra® tablets), and the selected optimized ODF formulation.

Pharmacokinetic parameter	Marked formula (Viagra® tablets)	Optimized sildenafil citrate ODF
Cmax (ng/ml)	215 ± 20.25	545 ± 31.34
tmax (hr)	1.25 ± 0.11	0.4 ± 0.07
AUC(0–24) (ng h/ml)	1135 ± 165	2205 ± 206
AUC(0–∞) (ng h/ml)	1190 ± 176	2415 ± 225
t1/2 (h)	3.5 ± 0.32	3.6 ± 0.41
Kel (h^−1)	0.27 ± 0.043	0.29 ± 0.023