Preparation, in vitro release, and pharmacokinetics in rabbits of lyophilized injection of sorafenib solid lipid nanoparticles

Figures & data

Figure 1 Chemical structure of sorafenib.

Figure 2 Schematic representation of technological process of preparation of S-SLN.

Abbreviation: S-SLN, sorafenib solid lipid nanoparticle singular.

Table 1 Factors and levels of the orthogonal test

	A (mg)	B (mg)	C (mg)	D (mg)
1	6	110	150	160
2	8	160	250	210
3	10	210	350	260

Table 2 The scheme and results of L₉ (3⁴) orthogonal test

No	A	B	C	D	EE%
1	1	1	1	1	78.35
2	1	2	2	2	94.74
3	1	3	3	3	84.41
4	2	1	2	3	67.48
5	2	2	3	1	74.02
6	2	3	1	2	57.20
7	3	1	3	2	73.42
8	3	2	1	3	63.87
9	3	3	2	1	59.31
K1	257.50	219.25	199.42	211.68
K2	198.70	232.63	221.53	225.36
K3	196.60	200.92	231.85	215.76
K̄1	85.83	73.08	66.47	70.56
K̄2	66.23	77.54	73.84	75.12
K̄3	65.53	66.97	77.28	71.92
R	20.30	10.57	10.81	4.56

Note: Encapsulation efficiency (EE) was expressed as mean (n = 3).

Table 3 The results of variance analysis

Sources of variance	SS	df	MS	F	P
A	796.74	2	398.37	24.23	<0.05
B	168.95	2	84.47	5.14	>0.05
C	183.01	2	91.50	5.57	>0.05
D	32.88	2	16.44	1.00	>0.05
Error	32.88	2	16.44

Note: F_0.05 (2, 2) = 19.00.

Abbreviations: DF, degrees of freedom; F, F ratio; SS, sum of square of deviations; MS, mean square.

Figure 3 TEM photograph of S-SLN.

Abbreviation: S-SLN, sorefenib solid lipid nanopraticles.

Figure 4 Size distribution of S-SLN.

Abbreviation: S-SLN, sorefenib solid lipid nanopraticles.

Figure 5 Zeta potential distribution of S-SLN.

Abbreviation: S-SLN, sorefenib solid lipid nanopraticles.

Table 4 Fitting equation of the accumulative release percentage of sorafenib SLN in vitro

Models	Equations	r
Zero-order kinetics	Q = 0.0147 t + 0.0271	0.9271
One-order kinetics	ln(1-Q) = −0.0164 t−0.0263	0.9379
Higuchi equation	Q = 0.0671 t1/2–0.0375	0.9744
Weibull equation	ln ln [1/(1-Q)] = 0.6308 ln t−3.1033	0.9763
Ritger–Peppas equation	ln Q = 0.5958 ln t−3.1134	0.9739

Abbreviation: SLN, solid lipid nanopraticles.

Figure 6 In vitro release of sorafenib from SLN in pH 7.4 phosphate-buffer solution at 37°C ± 1°C.

Note: Data represent mean ± SD (n = 3).

Abbreviation: SLN, solid lipid nanopraticles.

Table 5 The appearance, dissolution time, solution color and mean particle size of the lyophilization powder of S-SLN

Numbers (lyophilized powder)	Appearance	Dissolution time (minute)	Solution color	Particle size (nm)
S-SLN	Milky, leavening and porous, edge of scattering-like	2.0	Milky, translucent, clarified	Two peaks: 111.41 ± 3.20 and 531.03 ± 4.71
Mannitol	White like snow, dense surface, like pie	5.0	Translucent, clarified, microsmall amount of precipitate	141.34 ± 2.71
Trehalose	Similar to the color of trehalose, leavening and porous surface, closely packed like foam	2.5	Translucent, clarified, small amount of particles	222.53 ± 6.44
Mannitol + trehalose (1:1, v/v)	Milky, leavening and porous, edge of grid	3.0	Clarified, small amount of precipitate	331.02 ± 3.61

Abbreviation: SLN, solid lipid nanopraticles.

Figure 7 DSC thermograms of (A) egg-phophatidylcholine, (B) S-SLN, (C) glycerin behenate, (D) physical mixture of poloxamer188, sorafenib, glycerin behenate, EPC, (E) sorafenib and (F) poloxamer 188.

Abbreviations: DSC, differential scanning calorimetry; EPC, egg-phosphatidylcholine; S-SLN, sorafenib solid lipid nanoparticle.

Table 6 The results of accuracies

Theoretic	Intraday
Concentration (μg/mL)	Detectable concentration (μg/mL)
20.0	20.04 ± 0.30	20.38 ± 0.94
2.0	1.96 ± 0.02	1.98 ± 0.07
0.2	0.21 ± 0.01	0.24 ± 0.01

Note: Mean ± standard deviation, n = 5.

Table 7 The results of method recovery in plasma (n = 3)

Added (μg/mL)	Found (μg/mL)	Recovery (%)	Mean (%)	RSD (%)
20.0	20.55	102.75
20.0	19.85	99.25	100.78	1.78
20.0	20.07	100.35
2.0	1.95	97.50
2.0	2.07	103.50	100.33	3.00
2.0	2.00	100.00
0.2	0.21	105.00
0.2	0.21	105.00	106.67	2.71
0.2	0.22	110.00

Abbreviation: RSD, relative standard deviation.

Figure 8 HPLC chromatogram of (A) sorafenib control in blank plasma, (B) plasma sample after S-SLN administration and (C) blank plasma.

Abbreviations: HPLC, high-performance liquid chrematography; S-SLN, sorafenib solid lipid nanopraticle.

Table 8 Plasma pharmacokinetic parameters after intravenous administration of sorafenib solution in rabbits (n = 4)

Parameters	Value	SE
A (mg/L)	5.13	1.39
α (h^−1)	1.09	0.38
B (mg/L)	1.53	0.55
β (h^−1)	0.20	0.04
VC (L/kg)	3.00
t1/2α (h)	0.63
t1/2β (h)	3.44
K21 (h^−1)	0.41
K10 (h^−1)	0.54
K12 (h^−1)	0.35
AUC [(mg/L)·h]	12.29
CLs [(mg/kg)/h/(mg/L)]	1.63

Abbreviations: AUC, area under curve; CLs, clearance rates.

Table 9 The plasma pharmacokinetic parameters after intravenous administration of S-SLN in rabbits (n = 4)

Parameters	Value	SE
C0 (mg/L)	2.12	0.07
Ke (h^−1)	0.02	0.00
VC (L/kg)	9.45
t1/2(Ke) (h)	28.50
AUC [(mg/L)·h]	87.06
CLs [(mg/kg)/h/(mg/L)]	0.23

Abbreviations: AUC, area under curve; CLs, clearance rates.

Figure 9 The mean concentration-time curve of sorafenib in plasma after iv administration sorafenib and S-SLN in rabbits (n = 4).

Abbreviation: S-SLN, sorafenib solid lipid nanoparticle.

RavandiFCortesJEJoneDPhase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemiaJ Clin Oncol201028111856186220212254

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