Enhanced solubility and oral absorption of sirolimus using D-α-tocopheryl polyethylene glycol succinate micelles

Figures & data

Figure 1. Effect of TPGS on the solubility of sirolimus.

Table I. TPGS CMC and sirolimus S_free and K_a in the TPGS-sirolimus system.

Temperature	TPGS CMC (mg/mL)	Sfree (mg/mL)	Ka (mg/mL)^− 1
25°C	0.1	0.0929	3.30
37°C	0.1	0.1170	2.31

CMC, critical micelle concentration; S_free, free sirolimus concentration; and K_a, equilibrium distribution coefficient.

Figure 2. Effect of TPGS on the stability of sirolimus.

Figure 3. The pseudo-first-order degradation constant of sirolimus in a dissolution medium with a pH of 1.2.

Table II. The effect of the TPGS concentration on the stability of sirolimus in a dissolution medium with a pH of 1.2.

TPGS concentration (mg/mL)	kobs (min^−1)	t1/2 (min)
0 0.01 0.02 0.05 0.1 0.2 0.5 1 2 5 10	0.1347 0.0944 0.0798 0.0548 0.0424 0.0224 0.0126 0.0070 0.0043 0.0031 0.0012	5.15 7.34 8.68 12.64 16.35 30.99 55.01 99.64 161.78 224.56 560.13

The pseudo-first-order rate constants (kobs) and half-life (t_1/2) were calculated according to the equations ln[C_t] = ln[C₀] = kobs·= t and t_1/2 = 0.693/kobs, respectively. The data represent the mean of three independent experiments.

Figure 4. Representative Lineweaver–Burk plots for the degradation of sirolimus in a dissolution medium with a pH of 1.2.

Table III. The k₀, k_c and K_c values calculated using the Lineweaver–Burk plots for the TPGS-sirolimus system.

	k0 (min^−1)	kc (min^−1)	k0/kc	Kc (mM^−1)
Phase 1	0.1347	0.0304	4.43	93.25
Phase 2	0.1347	0.0011	125.63	34.74
Overall	0.1347	0.0108	12.46	69.21

Figure 5. Particle size distributions of empty TPGS micelles (a) and sirolimus-loaded TPGS micelles (b).

Table IV. Pharmacokinetic parameters of sirolimus in rats after the oral administration of raw sirolimus and sirolimus-loaded TPGS micelles.

Formulation	Pharmacokinetic parameter^a
	Cmax (ng/ml)	AUC0→12h (ng × hr/ml)	Tmax (hr)
Raw material	7.9 ± 2.8	55.0 ± 9.2	2.5 ± 1.3
Sirolimus loaded TPGS micelles	150.8 ± 33.5^*	745.9 ± 159.1^*	1.4 ± 0.5

^*Statistically significant difference (P < 0.05) when compared with the raw material. The data are expressed as the mean ±SD (n = 4).

^*The data are expressed as the mean ±} SD (n = 4).

Figure 6. Blood concentration–time profile of sirolimus in rats after the oral administration of raw sirolimus and sirolimus-loaded TPGS micelles.