Preparation of finasteride capsules-loaded drug nanoparticles: formulation, optimization, in vitro, and pharmacokinetic evaluation

Figures & data

Table 1 Draper–Lin small composite design studied variables, response, and their levels

Studied variables	Variables level
	High	Medium	Low
X1 (%)	1	0.65	0.3
X2 (%)	35	22.5	10
X3 (rpm)	20,000	15,000	10,000
X4 (minutes)	15	10	5
Responses	Aim
Y1 (nm)	Minimize
Y2 (%)	Maximize

Abbreviations: X1, stabilizer concentration; X2, miscible solvent ratio; X3, homogenization speed; X4, homogenization time; Y1, particle size; Y2, solubility enhancement.

Table 2 Draper–Lin small composite design formulations and the observed values of the studied responses

Run	X1 (%)	X2 (%)	X3 (rpm)	X4 (min)	Y1 observed	Y1 fit	Y2 observed	Y2 fit
1	0.65	22.5	15,000	1.59	2,280	2,319.09	19.48	14.48
2	0.3	10	10,000	5	1,977	1,954.77	25.74	30.20
3	1	10	10,000	15	2,735	2,712.77	15.94	20.40
4	1	35	10,000	5	3,955	3,932.77	13.27	17.73
5	0.65	43.52	15,000	10	3,767	3,806.09	13.45	8.45
6	0.061	22.5	15,000	10	2,356	2,395.09	18.94	13.94
7	0.3	35	20,000	15	2,076	2,042.96	20.53	23.13
8	0.65	22.5	23,409	10	1,688	1,739.94	56.87	54.08
9	0.65	22.5	15,000	18.41	2,508	2,547.09	18.54	13.54
10	1	35	20,000	5	2,827	2,793.96	16.84	19.44
11	0.65	1.478	15,000	10	745	784.088	146.41	141.41
12	0.3	10	20,000	5	934	900.956	139.86	142.46
13	0.3	35	10,000	15	2,310	2,287.77	19.85	24.311
14	1	10	20,000	15	2,357	2,323.96	18.81	21.41
15	1.24	22.5	15,000	10	2,841	2,880.09	15.67	10.67
16	0.65	22.5	6,591	10	2,902	2,928.23	13.43	6.22
17	0.65	22.5	15,000	10	2,601	2,560.71	16.11	21.89
18	0.65	22.5	15,000	10	2,612	2,560.71	15.98	21.89

Note: Each reading for Y1 and Y2 represents an average of three runs with SD <5% of the mean.

Abbreviations: X1, stabilizer concentration; X2, miscible solvent ratio; X3, homogenization speed; X4, homogenization time; Y1, particle size (nm); Y2, solubility enhancement (%); SD, standard deviation.

Table 3 Estimated effects of factors, F-ratio, and associated P-values for the finasteride nanoparticles particle size (Y1) and solubility enhancement (Y2)

Factors	Y1			Y2
	Estimated effect	F-ratio	P-value	Estimated effect	F-ratio	P-value
X1	288.38	15.24	0.0298a	−1.95	0.04	0.8513
X2	1,796.89	591.67	0.0002a	−79.06	68.91	0.0037a
X3	−706.56	220.86	0.0007a	28.45	21.55	0.0188a
X4	135.57	3.37	0.1638	−0.56	0.00	0.9569
X1X1	54.36	1.13	0.3665	−6.78	1.05	0.3801
X1X2	189.32	3.85	0.1446	29.59	5.65	0.0978
X1X3	−57.25	0.85	0.4247	−27.09	11.44	0.0430a
X1X4	1,005.64	108.56	0.0019a	−46.59	14.02	0.0332a
X2X2	−187.82	13.44	0.0351a	37.50	32.24	0.0108a
X2X3	14.75	0.06	0.8276	−28.19	12.39	0.0389a
X2X4	−855.87	78.63	0.0030a	33.34	7.18	0.0751
X3X3	−160.24	9.78	0.0522a	5.84	0.78	0.4420
X3X4	389.75	39.37	0.0082a	−28.54	12.70	0.0377a
X4X4	−90.24	3.10	0.1764	−5.58	0.71	0.4605

Notes:

a Significant effect of the studied factors on each response. X1X1, X2X2, X3X3, and X4X4 are the quadratic terms for the factors; X1X2, X1X3, X1X4, X2X3, X2X4, and X3X4 are the interaction terms between the factors.

Abbreviations: X1, stabilizer concentration; X2, miscible solvent ratio; X3, homogenization speed; X4, homogenization time.

Figure 1 Standardized Pareto charts for the effect of the studied factors on Y1 and Y2.

Abbreviations: X1, stabilizer concentration; X2, miscible solvent ratio; X3, homogenization speed; X4, homogenization time; Y1, particle size (nm); Y2, solubility enhancement (%), X1X1, X2X2, X3X3, and X4X4 are the quadratic terms for the factors. X1X2, X1X3, X1X4, X2X3, X2X4, and X3X4 are the interaction terms between the factors.

Figure 2 Estimated response surfaces along with contour plots for the effect of the studied factors on the particle size (A and B) and solubility enhancement (C and D).

Abbreviations: X1, stabilizer concentration; X2, miscible solvent ratio; X3, homogenization speed; X4, homogenization time.

Figure 3 TEM image for the optimized finasteride nanoparticles formulation.

Abbreviation: TEM, transmission electron microscope.

Figure 4 DSC thermogram of finasteride, PVA, physical mixture, and finasteride in the optimum formulation.

Abbreviations: DSC, differential scanning calorimetry; PVA, polyvinyl alcohol.

Figure 5 FTIR spectra of finasteride, PVA, physical mixture, and finasteride in the optimum formulation.

Abbreviations: FTIR, Fourier-transformed infrared; PVA, polyvinyl alcohol.

Figure 6 XRPD patterns of pure finasteride and drug nanoparticles.

Abbreviation: XRPD, X-ray powder diffraction.

Table 4 Pharmacokinetic parameters of finasteride after administration of pure drug, drug microparticles, and optimized drug nanoparticles formulation of a single dose (0.4 mg/kg) given as oral suspension

Pharmacokinetic parameters	Pure drug suspension	Optimized nanoparticles	Drug microparticle
Cmax (ng/mL)	22.25	96	41.25
Tmax (h)	6	2	4
AUC0–t (ng/mL min)	14,590.8	53,296.1	25,682.9
AUC0–∞ (ng/mL min)	1,976.18	2,932.68	2,343.27
MRT (h)	698.372	498.425	597.134

Abbreviations: AUC, area under the time–concentration curve; C_max, maximum plasma concentration; MRT, mean residence time; T_max, time to reach C_max

Figure 7 Plasma concentration–time curve following oral administration of the optimized finasteride formulation, pure drug in comparison, and drug microparticles.

Notes: The data represent the mean ± standard deviation (n=4). *Significant difference between nanosuspension with the pure drug. ^#Significant difference between nanosuspension with the microparticles. ^&Significant difference between the pure drug and microparticles.