Applying Different Techniques to Improve the Bioavailability of Candesartan Cilexetil Antihypertensive Drug

Figures & data

Figure 1 Structure of candesartan.

Table 1 Methods and Polymers Used in Preparation of Solid Dispersions, Inclusion Complexes and Nanoparticles of CC

CC:Carrier	Method	CC:Carrier Ratio	Sample Code
CC:PVP K-30	Solvent Evaporation Method	1:1	F1
CC:PVP K-30		1:2	F2
CC:PVP K-30		1:4	F3
CC:PVP K-90		1:1	F4
CC:PVP K-90		1:2	F5
CC:PVP K-90		1:4	F6
CC:PEG 4000	Fusion Method	1:1	F7
CC:PEG 4000		1:2	F8
CC:PEG 4000		1:4	F9
CC:PEG 6000		1:1	F10
CC:PEG 6000		1:2	F11
CC:PEG 6000		1:4	F12
CC:PEG 8000		1:1	F13
CC:PEG 8000		1:2	F14
CC:PEG 8000		1:4	F15
CC:β-CD	Coevaporation Method	1:1M	IC1
CC:HP β-CD		1:1M	1C2
PVP K30	Nanoprecipitation Method	10%	S1
PVP K90		10%	S2

Figure 2 Phase solubility diagram of CC/β-CD and CC/HP-β-CD in water at 250°C.

Table 2 Average Particle Size of CC Nanoparticles

Sample No.	Mean Particle Size (nm)± SD	PDI
S1	291.5 ± 20.19	0.418
S2	238.9 ± 19.25	0. 320

Figure 3 Zeta potential (ζ) of the prepared nanoparticles: (A) S1 and (B) S2.

Figure 4 TEM images of the prepared nanoparticles: (A) S1 and (B) S2.

Figure 5 X-ray diffraction patterns of (A) CC, (B) PVP-K90, (C) PM with PVP-K90, (D) SD with PVP-K90, (E) PEG8000, (F) PM with PEG 8000, (G) SD with PEG 8000, (H) HP-β-CD, (I) PM with HP β-CD, (J) IC with HP β-CD, (K) PM with PVP-K30, (L) nano with PVP-K30, (M) PM with PVP-K90, and (N) nanoparticles with PVP-K90.

Figure 6 FT-IR of (A) CC, (B) PVP-K90, (C) PM with PVP-K90, (D) SD with PVP-K90, (E) PEG8000, (F) PM with PEG 8000, (G) SD with PEG 8000, (H) HP-β-CD, (I) PM with HP β-CD, (J) IC with HP β-CD, (K) PM with PVP-K30, (L) Nano with PVP-K30, (M) PM with PVP-K90, and (N) nanoparticles with PVP-K90.

Figure 7 DSC thermograms of (A) CC, (B) PVP-K90, (C) PM with PVP-K90, (D) SD with PVP-K90, (E) PEG8000, (F) PM with PEG 8000, (G) SD with PEG 8000, (H) HP-β-CD, (I) PM with HP β-CD, (J) IC with HP β-CD, (K) PM with PVP-K30, (L) Nano with PVP-K30, (M) PM with PVP-K90, and (N) nanoparticles with PVP-K90.

Figure 8 The 3D structures of CC and two cyclodextrins (β-CD and HP-β-CD), showing the predicted orientations of CC within the hydrophobic cavity of β-CD (A) and HP-β-CD (B) from the side view as well as its binding interactions with the hydrophilic edges of β-CD (C) and HP-β-CD (D) as stick molecular depiction. Hydrogen bonds and hydrophobic interactions are demonstrated as black and red dashed lines, respectively.

Figure 9 Issolution rate of (A) CC/PVP-K30, (B) CC/PVP-K90, (C) CC/PEG4000, (D) CC/PEG6000, (E) CC/PEG8000, (F) CC/CD, and (G) CC/NP. Data represent mean cumulative % released ± SEM.

Figure 10 UPLC MS/MS spectrum of Candesartan and the I.S. (Pitavatatin) showing the retention time of CC and I.S.

Table 3 Pharmacokinetic Parameters of Candesartan in Plasma of Rabbit After Oral Administration of 20 Mg of CC as a Solid Dispersion and CC Alone.

Pharmacokinetic Parameter	Unit	CC (SDs)	CC Alone
Cmax	ng/mL	135.32 ± 2.11	44.22 ± 1.35
Tmax	h	1.69 ± 0.13	1.75 ± 0.17
AUC0-inf	ng/mL·h	342.82 ± 13.57	159.32 ± 12.74
A	ng/mL	3196 ± 26.66	1570 ± 35.38
K	h^−1	0.545 ± 0.08	0.555 ± 0.04
Ka	h^−1	0.579 ± 0.04	0.589 ± 0.06
AUMC0-inf	ng/mL·h^2	1217.8 ± 25.46	570.23 ± 19.11
MRT	h	3.51 ± 0.14	3.49 ± 0.18

Data are presented as mean ± SEM.

Figure 11 Concentration-time profiles of CC alone and in SDs with PVP K-90 (data displayed±SEM).