Etodolac transdermal cubosomes for the treatment of rheumatoid arthritis: ex vivo permeation and in vivo pharmacokinetic studies

Figures & data

Table 1. Composition and characterization parameters values for etodolac loaded cubosomes nanoparticles.

Formula Code^a	Plx^b:MO^c Weight ratio	Plx^b (%w/w)	MO^c (%w/w)	Plx^b and MO^c:Water Weight ratio	Particle size (nm)	Zeta potension (mV)	Loading capacity (%)	Viscosity (cp)
F1	–	0.00	4.76	1:20	223.45 ± 4.03	–18.40 ± 1.27	6.09 ± 8.11	3.14 ± 0.16
F2	1:6	0.68	4.08	1:20	182.85 ± 5.64	–33.95 ± 2.19	3.89 ± 5.25	3.14 ± 0.12
F3	1:4	0.96	3.80	1:20	178.70 ± 7.70	–31.75 ± 0.92	3.93 ± 5.24	3.14 ± 0.13
F4	1:2	1.58	3.18	1:20	142.35 ± 5.49	–31.85 ± 0.78	3.87 ± 5.27	3.66 ± 0.25
F5	–	0.00	9.10	1:10	288.35 ± 3.89	–32.70 ± 0.14	3.60 ± 4.58	3.66 ± 0.32
F6	1:6	1.30	7.80	1:10	184.65 ± 4.92	–32.35 ± 0.49	2.52 ± 2.59	3.14 ± 0.15
F7	1:4	1.82	7.28	1:10	162.35 ± 3.46	–31.00 ± 0.71	2.23 ± 2.83	4.71 ± 0.41
F8	1:2	3.04	6.06	1:10	135.95 ± 5.21	–33.95 ± 0.49	2.08 ± 2.50	4.71 ± 0.43
F9	–	0.00	16.66	1:5	248.10 ± 4.38	–28.20 ± 0.14	2.16 ± 2.45	6.80 ± 0.72
F10	1:6	2.38	14.28	1:5	219.50 ± 6.79	–33.60 ± 0.28	1.28 ± 1.75	75.86 ± 5.42
F11	1:4	3.34	13.32	1:5	197.90 ± 9.90	–36.10 ± 2.97	1.74 ± 2.06	80.57 ± 7.05
F12	1:2	5.56	11.10	1:5	162.5 ± 3.72	–32.70 ± 0.99	1.64 ± 1.95	85.58 ± 4.25

Etodolac was used in concentration of 2% w/w.

^a The aqueous solution contained 2.5%w/w poly(vinyl alcohol) was added to the formulation to get 100% w/w.

^b Plx: Poloxamer 407.

c MO: Monoolein.

Table 2. Release parameter values for etodolac-loaded cubosomes nanoparticles.

		Release data according to Korsmeyer–Peppas model
Formula code	Release efficiency (RE %)	n-value	Release rate (K; %/hr)	t50 (hr)	t90 (hr)
F1	16.21 ± 0.86	0.68 ± 0.05	6.86 ± 0.47	10.79 ± 0.04	19.40 ± 0.10
F2	19.35 ± 3.59	0.72 ± 0.02	8.47 ± 1.24	8.49 ± 0.94	15.09 ± 1.55
F3	25.72 ± 3.30	0.71 ± 0.06	10.68 ± 1.05	6.79 ± 0.13	12.09 ± 0.17
F4	32.58 ± 0.87	0.64 ± 0.06	15.08 ± 4.28	5.53 ± 0.96	9.80 ± 1.80
F5	12.66 ± 2.09	0.69 ± 0.09	5.87 ± 1.69	12.54 ± 0.94	22.42 ± 1.60
F6	16.72 ± 2.55	0.79 ± 0.03	5.41 ± 0.31	12.00 ± 1.03	21.36 ± 1.92
F7	22.54 ± 0.24	0.77 ± 0.01	6.74 ± 0.25	10.08 ± 0.20	17.83 ± 0.39
F8	21.23 ± 4.16	0.82 ± 0.16	5.53 ± 2.15	11.45 ± 1.36	20.23 ± 2.07
F9	11.41 ± 0.10	0.78 ± 0.00	3.30 ± 0.03	19.84 ± 0.18	35.37 ± 0.33
F10	4.62 ± 0.05	0.62 ± 0.02	2.23 ± 0.12	36.17 ± 0.91	65.13 ± 1.59
F11	5.43 ± 0.05	0.61 ± 0.02	2.65 ± 0.94	30.78 ± 0.78	55.49 ± 1.69
F12	5.22 ± 0.04	0.79 ± 0.03	1.68 ± 0.10	38.02 ± 0.79	68.19 ± 1.30

Figure 1. Transmission electron microscopy (TEM) images of etodolac cubosomes nanoparticles: a and b for F3 and c and d for F4.

Figure 2. Physicochemical characterization for cubosomes nanoparticles: (A) DSC thermograms of (1) etodolac, (2) monoolein, (3) PVA and (4) poloxamer 407 as well as cubosomes formulations (5) F3 and (6) F4; (B) X-ray diffraction of etodolac as well as cubosomes formulations F3 and F4.

Figure 3. Permeation of etodolac from F3 and F4 cubosomes nanoparticles through excited mice skin.

Figure 4. Etodolac mean plasma concentration (ng/ml) after oral administration of capsules and transdermal application of F3 and F4 cubosomal formulations to healthy human volunteers.