Enhanced transdermal delivery of carvedilol using nanoemulsion as a vehicle

Figures & data

Table 1. Solubility of carvedilol in various vehicles (oils, surfactants and water).

Oil	Solubility (mg/ml)	Surfactants	Solubility (mg/ml)	Surfactants/ vehicle	Solubility (mg/ml)
Oleic acid	105.29 ± 13.72	Acconon CC6®	44.32 ± 6.89	Transcutol P®	184.02 ± 21.03
Capmul PG8®	27.47 ± 5.13	Labrasol®	53.05 ± 7.84	Plurol isostearique®	8.56 ± 1.10
Miglyol 810®	31.46 ± 4.27	Tween 80	21.50 ± 2.06	PEG-200	31.38 ± 9.49
Labrafil M 2125®	21.17 ± 1.06	Cremophore RH40®	11.06 ± 1.38	PEG-400	43.33 ± 3.15
Olive oil	7.20 ± 0.43	Tween 20	17.72 ± 6.14	Propylene glycol	7.31 ± 0.86
IPP	4.89 ± 0.56	Span 20	3.1 ± 0.31	Ethanol	10.74 ± 0.99
IPM	3.72 ± 0.12	CO-20®	22.78 ± 2.15	Water	Not detectable
Labrafil M 1944®	22.36 ± 2.13	Lauroglycol 90®	9.42 ± 0.94
Note: mean ± SD; n = 3.

Table 2. The surfactant nanoemulsification efficiency (S _min) and percentage transmittance for oils investigated after 24 h.

Oils	Surfactants
	Labrasol®		Acconon CC6®		Tween 80
	S min (%)	Transmittance (%)	S min (%)	Transmittance (%)	S min (%)	Transmittance (%)
Labrafil M1944®	54.05	99.32	54.55	99.47	76.47	95.72
Labrafil M2125®	60.00	98.45	55.55	99.39	77.27	94.87
Oleic acid	78.72	93.02	73.33	94.57	69.23	96.81
Capmul PG8®	75.00	94.31	59.54	98.66	37.50	99.37
Miglyol 810®	60.94	97.73	46.52	99.71	63.63	97.32
Olive oil	90.00	78.94	83.60	80.05	–	–

Table 3. The co-surfactants nanoemulsification efficiency (S/CoS _min) and percentage transmittance for Miglyol 810® oils after 24 h.

Co-surfactants	HLB^a		Transmittance (%)
CO-20®	11.50	37.11	99.64
Plurol Oleique®	11.25	41.18	95.45
Labrasol®	13.25	45.94	96.31
Cremophore RH40®	13.50	40.37	96.82
Ethanol	–	60.94	95.72
Transcutol P®	8.25	73.19	96.32
Note: ^aHLB for equal mass mixture of Acconon CC6® and co-surfactants.
^bMinimum S/CoS mixture (at 1 : 1 ratio) required for solubilisation of equal mass mixture of Miglyol 810® and water.

Figure 1. Pseudo-ternary phase diagrams showing nanoemulsion existence range composed of Miglyol 810® (oil), Acconon CC6® (surfactant), water and different co-surfactants. (a) Transcutol P®; (b) Plurol Oleique®; (c) Labrasol®; (d) Cremophore RH40®; and (e) CO-20® at S/CoS 1 : 1 ratio.

Figure 2. Pseudo-ternary phase diagrams showing nanoemuslion existence range composed of Miglyol 810® (oil), Acconon CC6® (surfactant), CO-20® (co-surfactant) and water at different S/CoS ratios.

Figure 3. Nanoemulsion existence area obtained with Acconon CC6® as surfactant and CO-20® as co-surfactant at different S/CoS ratios in the pseudo-ternary phase diagrams.

Table 4. Nanoemulsion composition selected from pseudo-ternary phase diagram of S/CoS ratio 1 : 1 and the data for evaluation parameters like mean globules size, polydispersity index (PI), viscosity, refractive index (RI), pH and percentage transmittance.

Formulation	Oil (% w/w)	S/CoS (% w/w)	Water (% w/w)	Mean globules size (nm)	PI	Viscosity (cps)	RI	pH	Transmittance (%)
F1	10	50	40	11.32	0.118	54.83 ± 5.39	1.417 ± 0.008	6.5 ± 0.51	99.32
F2	12.5	50	37.5	9.28	0.103	58.07 ± 4.82	1.411 ± 0.011	6.4 ± 0.42	99.30
F3	15	50	35	21.54	0.137	59.64 ± 6.22	1.422 ± 0.010	6.0 ± 0.31	99.27
F4	17.5	50	32.5	84.94	0.298	81.34 ± 8.47	1.432 ± 0.011	5.8 ± 0.27	98.17
F5	20	50	30	95.47	0.319	105.76 ± 12.83	1.441 ± 0.012	5.6 ± 0.51	96.02
F6	10	45	45	23.7	0.209	57.18 ± 4.27	1.406 ± 0.009	5.8 ± 0.38	99.12
F7	10	40	50	25.82	0.202	53.07 ± 4.62	1.403 ± 0.011	5.9 ± 0.41	99.18
F8	10	35	55	36.27	0.238	34.83 ± 4.22	1.404 ± 0.015	5.6 ± 0.19	98.29

Figure 4. Micrograph of carvedilol nanoemulsion under transmission electron microscope (TEM).

Figure 5. The effect of amount of oil present in nanoemulsion on the permeation rate of carvedilol (mean value ± SD; n = 3).

Figure 6. The effect of amount of mixture of surfactants (S/CoS, 1 : 1) in nanoemulsions on the permeation rate of carvedilol (mean value ± SD; n = 3).

Table 5. Percutaneous permeation parameters of the nanoemulsion formulations across wistar rat skin.

Formulations	Cumulative amount (µg/cm^2)^a	Flux (µg/cm^2/h)^a	Pb (10^3 cm/h)^a	ER^b	T lag (h)
Water	189.34 ± 71.71	7.88 ± 1.21	3.15 ± 0.32	–	4.2 ± 0.78
Neat oil	670.51 ± 112.66	26.02 ± 2.29	10.41 ± 0.61	–	3.0 ± 0.56
Neat S/CoS	371.79 ± 61.35	14.87 ± 1.81	5.95 ± 0.65	–	3.2 ± 0.44
F1	2897.47 ± 213.42	130.40 ± 22.64	52.16 ± 4.12	5.0 ± 0.87	0.7 ± 0.010
F2	3516.33 ± 221.11	161.53 ± 23.65	64.61 ± 6.73	6.2 ± 1.21	0.5 ± 0.010
F3	3255.08 ± 312.29	149.15 ± 37.27	59.66 ± 5.18	5.7 ± 1.13	1.2 ± 0.021
F4	3040.94 ± 176.63	136.82 ± 33.65	54.73 ± 4.77	5.3 ± 0.91	1.5 ± 0.022
F5	2114.38 ± 191.26	92.251 ± 38.54	36.90 ± 6.39	3.5 ± 1.47	1.8 ± 0.029
F6	2781.84 ± 214.44	126.23 ± 21.83	50.49 ± 3.78	4.9 ± 0.89	0.2 ± 0.010
F7	2711.18 ± 151.71	122.65 ± 22.37	49.06 ± 6.18	4.7 ± 1.21	0.5 ± 0.011
F8	2402.82 ± 131.77	111.32 ± 23.26	44.53 ± 5.41	4.3 ± 1.22	0.5 ± 0.012
Notes: mean ± SD; n = 3.
^aData for formulation F1–F8 is statistically significant (p < 0.05) in comparison with control vehicles (water, neat oil and neat S/CoS).    ^bEnhancement ratio (ER) for formulation F1–F8 in comparison to neat oil as control and were found significant (p < 0.05).

Figure 7. A comparative profile showing effect of mean globules size on skin permeation rate (flux) and on lag time (mean globule size presented in parenthesis of nanoemulsion formulation coded on x-axis).