Design and evaluation of oral nanoemulsion drug delivery system of mebudipine

Figures & data

Figure 1. Solubility of MB in various oils. Data expressed as mean ± SD (n = 3).

Figure 2. Solubility of mebudipine in various solvent. Data expressed as mean ± SD (n = 3).

Table 1. Mean (±S.D.) percentage transmittance of formulation with different Smix at 650 nm, 25 °C (n = 3).

Component of Smix in formulation	%T
T20 + S80 + PEG	55.3 ± 1.5
T20 + S80 + Etoh	66.5 ± 1.8
T20 + S80 + PEG + Etoh	26.6 ± 1.1
T80 + S80 + PEG	62.7 ± 2.5
T80 + S80 + Etoh	81.8 ± 1.6
T80 + S80 + PEG + Etoh	99.0 ± 0.1

Figure 3. Pseudo-ternary diagram of system with different ratio of surfactant (T80 + S80) to co-surfactant (PEG + Etoh) indicating O/W nanoemulsion region at different Smix ratios. (A) Smix ratio = 1:0; (B) Smix ratio = 1:1; (C) Smix ratio = 1:2; (D) Smix ratio = 1:3; (E) Smix ratio = 2:1.

Figure 4. Pseudo-ternary diagram indicating O/W nanoemulsion region at different co- surfactant ratio. (A) PEG/Etoh = 1/1; (B) PEG/Etoh = 2/1; (C) PEG/Etoh = 1/2; (D) PEG/Etoh = 3/1.

Table 2. Thermodynamic stability test of different formulations selected from phase diagram.

		Percentage (w/w) of different components			Observation based on thermodynamic stability study
Phase diagram	PEG/Etoh	Oil	Smix	Aqueous	H/C	Cent.	Freez.Tha
A	1:1	10	30	60	√	√	×
A	1:1	10	45	35	√	√	√
A	1:1	15	35	50	×	√	×
B	2:1	10	40	50	√	√	√
B	2:1	10	50	40	√	√	√
B	2:1	20	50	20	×	√	×

H/C: Heating-cooling cycle; cent: Centrifugation; Freez.Tha: Freeze thaw cycle.

√: Passed; ×: Failed.

Table 3. Composition, droplet size and polydispersity index of selected nanoemulsion formulations.

			Percentage (w/w) different components in formulation			Mean droplet size ± S.D. (nm)		PDI ± S.D.
Code	Smix* Ratio	PEG/Etoh	Oil	Smix	Aqueous	Day 1	Month 3	Day 1	Month 3
MF1	1:1	2:1	10	40	50	28.2 ± 3.7	57.6 ± 9.0	0.35 ± 0.03	0.37 ± 0.05
MF2	1:1	2:1	10	50	40	22.8 ± 4.0	35.9 ± 5.5	0.39 ± 0.04	0.26 ± 0.08
MF3	1:1	1:1	10	45	35	35.1 ± 5.2	59.0 ± 7.2	0.36 ± 0.07	0.45 ± 0.10

*Smix indicates mixture of surfactant and co-surfactant in specific volume ratio.

Figure 5. Transmission electron micrograph of MB nanoemulsion.

Figure 6. Drug-concentration time profiles of various mebudipine (MB) formulations after oral administration to rats (n = 6, dose = 10 mg/kg).

Table 4. Pharmacokinetic parameters upon oral administration of various mebudipine formulations (10 mg/kg) to rats.

Pharmacokinetic parameters	Suspension	Oily solution	Micellar solution	Nanoemulsion
Cmax (ng/ml)	37.8 ± 8.8	56.0 ± 14.5	63.8 ± 9.5	116.8 ± 26.0^a,b,c
Tmax (h)	0.55 ± 0.22	0.83 ± 0.40	0.58 ± 0.20	0.66 ± 0.25
T1/2(h)	3.87 ± 1.41	4.07 ± 0.96	2.41 ± 0.65	3.43 ± 0.90
AUC0→6 (ng h/ml)	79.3 ± 15.3	105.6 ± 18.4	128.9 ± 16.2^d	221.4 ± 32.4^a,b,c
AUC0→∞ (ng h/ml)	112.7 ± 16.6	147.8 ± 28.1	153.2 ± 19.6	297.3 ± 29.6^a,b,c

Data expressed as mean ± S.D., n = 6.

^aSignificantly higher (p < 0.001) compared to MB suspension.

^bSignificantly higher (p < 0.001) compared to MB oily solution.

^cSignificantly higher (p < 0.001) compared to MB micellar solution.

^dSignificantly higher (p < 0.05) compared to MB suspension and oily solution.