Pharmacokinetics and enhanced oral bioavailability in beagle dogs of cyclosporine A encapsulated in glyceryl monooleate/poloxamer 407 cubic nanoparticles

Figures & data

Table 1 Formulation details and properties of CyA-loaded cubic nanoparticles

Poloxamer 407/GMO ratio	Theoretical solid content (%, w/v)a	Theoretical drug loading (%)b	Particle size (nm)	Polydispersity	Entrapment efficiency (%)
12/100	11.4	1.75	136.4 ± 5.8	0.291	91.45 ± 1.45

Notes:

a Calculated as the weight ratio of (GMO + poloxamer 407) to total sample (GMO + poloxamer 407 + water);

b Calculated as the weight ratio of CyA to total solids (CyA + GMO + poloxamer 407).

Figure 1 Cryo-TEM photographs of blank A) and CyA-loaded B) cubic nanoparticles. The bars equal 200 nm.

Figure 2 Size distribution of CyA-loaded cubic nanoparticles after sonication A) and homogenization at 689 bar for five cycles B).

Figure 3 Effect of GMO/poloxamer 407 ratio A) and homogenization pressure and cycles B) on mean diameter of CyA-loaded cubic nanoparticles (n = 3).

Note: *P < 0.01 compared to any other group.

Figure 4 Effect of GMO/poloxamer 407 ratios A) and homogenization pressure and cycles B) on entrapment efficiency of CyA-loaded cubic nanoparticles (n = 3).

Notes: *P < 0.05 as compared to any other group; **P < 0.05 as compared to any other group except these two groups.

Figure 5 Release profiles of CyA-loaded GMO/poloxamer 407 cubic nanoparticles and Neoral^® capsules (n = 3).

Figure 6 Beagle dog plasma CyA concentrations versus time plot after a single oral dose of 100 mg equivalent CyA cubic nanoparticles or Sandimmun Neoral^® (n = 6).

Table 2 Pharmacokinetic parameters after oral administration of CyA-loaded cubic nanoparticles and Sandimmun Neoral^® calculated by a noncompartmental method

Formulation	tmax (h)	Cmax (ng mL^−1)	t1/2 (h)	AUC0–t (ng h mL^−1)	AUC0–∞ (ng h mL^−1)	MRT (h)	Relative bioavailability (%)*
Cubic nanoparticles	2.42 ± 0.80	1371.18 ± 357.34	12.14 ± 8.37	7757.21 ± 1093.64	9004.77 ± 1090.38	6.56 ± 1.08	177.92 ± 47.68
Sandimmun Neoral^®	1.83 ± 0.75	969.68 ± 176.30	22.29 ± 10.54	4739.52 ± 806.30	5462.31 ± 990.76	6.39 ± 0.70

Note:

* Calculated on AUC_0–∞ with Sandimmun Neoral^® as reference.

Table 3 Pharmacokinetic parameters after oral administration of CyA-loaded cubic nanoparticles and Sandimmun Neoral^® calculated by a two-compartmental method

Formulation	ka (h^−1)	α (h^−1)	β (h^−1)	t1/2(α) (h)	t1/2(β) (h)	t1/2(a) (h)	k10 (h^−1)	k12 (h^−1)	k21 (h^−1)
Cubic nanoparticles	0.52 ± 0.076	0.24 ± 0.068	0.062 ± 0.056	3.05 ± 0.90	12.14 ± 8.37	1.46 ± 0.37	0.096 ± 0.047	0.081 ± 0.10	0.13 ± 0.10
Sandimmun Neoral^®	0.73 ± 0.37	0.41 ± 0.12	0.032 ± 0.022	1.84 ± 0.57	22.29 ± 10.54	1.14 ± 0.61	0.10 ± 0.054	0.19 ± 0.10	0.14 ± 0.17