Experimental, molecular docking investigations and bioavailability study on the inclusion complexes of finasteride and cyclodextrins

Figures & data

Figure 1 Structural formula of FIN.

Abbreviation: FIN, finasteride.

Table 1 Pharmacokinetic parameters of FIN in plasma of rabbits after oral administration of 1 mg FIN/kg or its equivalent amount from FIN/DM-β-CyD coprecipitate

Pharmacokinetic parameters	FIN	FIN/DM-β-CyD
Ka (h^−1)	0.757±0.156	1.452±0.238
Ke (h^−1)	0.062±0.012	0.058±0.017
AUC (ng⋅h⋅mL^−1)	781.52±93.74	1,339.05±133.17
Tmax (h)	3.5±0.37	2.58±0.24
Cmax (ng/mL)	39.25±9.92	63.55±11.14
t1/2 (h)	11.02±2.17	12.62±1.73

Abbreviations: K_a, absorption rate constant; K_e, elimination rate constant; AUC, area under the curve; T_max, time to reach maximum concentration; C_max, maximum concen tration; t_1/2, elimination half-life; FIN, finasteride; DM-β-CyD, dimethyl-β-cyclodextrin.

Figure 2 Plasma level–time curve of orally administered 1 mg/kg of raw FIN and its equivalent amount of DM-β-CyD coprecipitated system given to rabbits.

Abbreviations: FIN, finasteride; DM-β-CyD, dimethyl-β-cyclodextrin.

Table 2 FIN solubility (S₀), slope, correlation coefficient (R), stability constant (K_c), and CE from phase solubility diagrams

System	S0 (mM)	Slope	R	Kc (mM^−1)	CE
FIN/β-CyD	0.264	0.017	0.818	0.066	0.0173
FIN/HP-β-CyD	0.267	0.178	0.996	0.811	0.217
FIN/CM-β-CyD	0.116	0.169	0.997	1.753	0.203
FIN/SBE-β-CyD	0.206	0.200	0.998	1.213	0.250
FIN/DM-β-CyD	0.248	0.322	0.998	1.915	0.475

Abbreviations: FIN, finasteride; CE, complexation efficiency; β-CyD, β-cyclodextrin; HP-β-CyD, hydroxypropyl-β-CyD; CM-β-CyD, carboxymethyl-β-cyclodextrin; SBE-β-CyD, sulfobutyl ether-β-cyclodextrin; DM-β-CyD, dimethyl-β-cyclodextrin.

Figure 3 Phase solubility diagrams of FIN in the presence of β-CyD, CM-β-CyD, SBE-β-CyD, HP-β-CyD, and DM-β-CyD.

Abbreviations: FIN, finasteride; β-CyD, β-cyclodextrin; CM-β-CyD, carboxymethyl-β-cyclodextrin; SBE-β-CyD, sulfobutyl ether-β-cyclodextrin; HP-β-CyD, hydroxypropyl-β-CyD; DM-β-CyD, dimethyl-β-cyclodextrin; CyD, cyclodextrin.

Figure 4 FTIR spectra of 1) FIN; 2) DM-β-CyD, its physical mixture with FIN (PM), and its coprecipitated complex (Coppt); 3) HP-β-CyD, its PM, and its Coppt; 4) SBE-β-CyD, its PM, and its Coppt; 5) CM-β-CyD, its PM, and its Coppt; and 6) β-CyD, its PM, and its Coppt.

Abbreviations: FTIR, Fourier transform infrared spectroscopy; FIN, finasteride; DM-β-CyD, dimethyl-β-cyclodextrin; HP-β-CyD, hydroxypropyl-β-CyD; SBE-β-CyD, sulfobutyl ether-β-cyclodextrin; CM-β-CyD, carboxymethyl-β-cyclodextrin; β-CyD, β-cyclodextrin; PM, physical mixture.

Figure 5 Powder XRD patterns of 1) FIN; 2) DM-β-CyD, its physical mixture with FIN (PM), and its coprecipitated complex (Coppt); 3) HP-β-CyD, its PM, and its Coppt; 4) SBE-β-CyD, its PM, and its Coppt; 5) CM-β-CyD, its PM, and its Coppt; and 6) β-CyD, its PM, and its Coppt.

Abbreviations: XRD, X-ray diffractometry; FIN, finasteride; DM-β-CyD, dimethyl-β-cyclodextrin; HP-β-CyD, hydroxypropyl-β-CyD; SBE-β-CyD, sulfobutyl ether-β-cyclodextrin; CM-β-CyD, carboxymethyl-β-cyclodextrin; β-CyD, β-cyclodextrin; PM, physical mixture.

Figure 6 DSC thermograms of 1) FIN; 2) DM-β-CyD, its physical mixture with FIN (PM), and its coprecipitated complex (Coppt); 3) HP-β-CyD, its PM, and its Coppt; 4) SBE-β-CyD, its PM, and its Coppt; 5) CM-β-CyD, its PM, and its Coppt; and 6) β-CyD, its PM, and its Coppt.

Abbreviations: DSC, differential scanning calorimetry; FIN, finasteride; DM-β-CyD, dimethyl-β-cyclodextrin; HP-β-CyD, hydroxypropyl-β-CyD; SBE-β-CyD, sulfobutyl ether-β-cyclodextrin; CM-β-CyD, carboxymethyl-β-cyclodextrin; β-CyD, β-cyclodextrin; PM, physical mixture.

Figure 7 Binding mode of FIN (blue sticks) into DM-β-CyD (A), HP-β-CyD (B), SBE-β-CyD (C), CM-β-CyD (D), and β-CyD (E).

Abbreviations: FIN, finasteride; DM-β-CyD, dimethyl-β-cyclodextrin; HP-β-CyD, hydroxypropyl-β-CyD; SBE-β-CyD, sulfobutyl ether-β-cyclodextrin; CM-β-CyD, carboxymethyl-β-cyclodextrin; β-CyD, β-cyclodextrin.

Figure 8 Dissolution profile of FIN (5 mg) as a raw material and as β-CyD, HP-β-CyD, SBE-β-CyD, CM-β-CyD, and DM-β-CyD coprecipitated systems in distilled water at 37°C±0.5°C (United States Pharmacopeia [USP]).

Abbreviations: FIN, finasteride; β-CyD, β-cyclodextrin; HP-β-CyD, hydroxypropyl-β-CyD; SBE-β-CyD, sulfobutyl ether-β-cyclodextrin; CM-β-CyD, carboxymethyl-β-cyclodextrin; DM-β-CyD, dimethyl-β-cyclodextrin.