Improvement of effect of water-in-oil microemulsion as an oral delivery system for fexofenadine: in vitro and in vivo studies

Figures & data

Table 1 The solubility of FEX in various vehicles at 25°C

Vehicles	FEX (mg/mL)
Water	1.58 ± 0.04
Oil
Oleic acid	6.15 ± 0.25
Surfactants
Lutrol F 68	24.95 ± 0.49
Span 80	12.28 ± 0.04
Isopropyl alcohol	29.55 ± 0.27

Abbreviation: FEX, fexofenadine.

Table 2 The contents of optimized microemulsion formulation

Formulation	Oil (%)	S1 (%)	S2 (%)	coS (%)	Water (%)
Microemulsion	34.05	1.49	28.31	29.79	6.36

Notes: S₁: Lutrol F 68, S₂: Span 80, coS: Isopropyl alcohol.

Figure 1 Pseudoternary phase diagrams of microemulsion system. (A) 1:1 S/coS ratio, (B) 2:1 S/coS ratio, (C) 3:1 S/coS ratio, (D) 4:1 S/coS ratio, (E) 5:1 S/coS ratio.

Table 3 Characterization of microemulsion

Samples	Electrical conductivity (μs cm^−1)	Viscosity η (cps)	Droplet size (nm)	Polydispersity	Zeta potential (mV)	Content of FEX mg/mL
A	1 ± 0.03	104.7 ± 0.15	39.05 ± 0.87	0.044 ± 0.01	−1.95 ± 0.12	–
B	1.1 ± 0.02	103.8 ± 0.25	33.29 ± 1.76	0.044 ± 0.02	−2.13 ± 0.21	5.98 ± 0.17

Notes: A: Microemulsion without FEX, B: Microemulsion with FEX.

Abbreviation: FEX, fexofenadine.

Table 4 Stablity of optimum microemulsion containing FEX (A) and (B)

Temperature/month	25°C		40°C
	Droplet size (nm)	Content of FEX (mg/mL)	Droplet size (nm)	Content of FEX (mg/mL)
(A)
0	33.29 ± 0.95	5.98 ± 0.17	33.29 ± 0.95	5.98 ± 0.17
3	33.72 ± 0.61	5.89 ± 0.24	34.01 ± 0.55	6.11 ± 0.12
6	33.34 ± 0.44	6.01 ± 0.16	34.72 ± 0.85	6.09 ± 0.35
	25°C	40°C
	Zeta potiential (mV)	Zeta potiential (mV)
(B)
0	2.13 ± 0.21	2.13 ± 0.21
3	2.1 ± 0.14	2.11 ± 0.2
6	2.01 ± 0.09	2.14 ± 0.15

Abbreviation: FEX, fexofenadine.

Table 5 The permeability value of FEX with different formulations (n = 6 ± SD)

Formulation	Papp A to B 10^−5(cm/s)	Papp B to A 10^−5(cm/s)	Papp B to A/Papp A to B ratio
SY	1.97 ± 0.23	2.39 ± 0.77	1.21
ME	2.55 ± 0.05	2.61 ± 1.33	1.02

Abbreviations: A, apical; B, basolateral; FEX, fexofenadine; ME, microemulsion; SD, standard deviation; SY, syrup.

Figure 2 The amount of FEX permeability across Caco-2 cell (n = 6 ± SD).

Notes: A to B for SY = The amount of FEX from apical to basolateral direction of syrup, B to A for SY = The amount of FEX from basolateral to apical direction of syrup, A to B for ME = The amount of FEX from apical to basolateral direction of microemulsion, B to A for ME = The amount of FEX from basolateral to apical direction of microemulsion.

Abbreviations: A, apical; B, basolateral; FEX, fexofenadine; ME, microemulsion; SD, standard deviation; SY, syrup.

Table 6 The % TEER change of experiments across Caco-2 cell for both directions with ± SD (A → B: Apical to basolateral direction, B → A basolateral to apical direction)

% TEER Change
SY		ME
A → B	B → A	A → B	B → A
−12.8 ± 0.23	−14.7 ± 0.88	−33.7 ± 2.76	−41.1 ± 3.21

Abbreviations: A, apical; B, basolateral; ME, microemulsion; SD, standard deviation; SY, syrup; TEER, transepithelial electrical resistance.

Table 7 Parameters of the fit of the models with passive component an Michaelis–Menten component and goodness of fit indexes

SY	Value	SD	CV%	ME	Value	SD	CV%
Pdif (cm/s)	2.24E-05	8.79E-08	3.92	Pdif (cm/s)	3.51 E-05	6.55 E-08	2.13
Km (μM)	681.5	260.56	38.23	Km (μM)	89345	310.42	36.17
Vm (nMol · cm^−2 · s^−1)	0.0132	0.000405	30.69	Vm (nMol · cm^−2 · s^−1)	0.0452	0.001105	23.46
SSR	1.30E-11			SSR	1.8E-11
AIC	−1046			AIC	−1087
Parameter	Value	SD	CV%	Parameter	Value	SD	CV%
Pdif (cm/s)	2.57E-05	1.23E-07	4.77	Pdif (cm/s)	3.42 E-05	0.92 E-07	5.22
Km (μM)	513.91	160.38	31.21	Km (μM)	634.76	145.87	25.29
Vm (nMol · cm^−2 · s^−1)	0.0147	0.000391	26.48	Vm (nMol · cm^−2 · s^−1)	0.0521	0.000198	27.81
A	2.79	0.86	30.82	A	3.11	0.56	25.31
SSR	9.10E-12			SSR	10.08E-12
AIC	−1059			AIC	−1098

Abbreviations: A, apical; B, basolateral; AIC, Akaike’s information criteria; CV, coefficient of variability; ME, microemulsion; Pdif, passive diffusion component; SD, standard deviation; SSR, sum of squared residuals; SY, syrup.

Note: Vm and Km are the Michaelis–Menten parameters.

Table 8 Pharmacokinetic results from curve fitting of in vivo plasma data after microemulsion and Fexofen^® syrup administration (n = 6) with SD

Samples	Tmax (hour)	t1/2 (hour)	Cmax (μg/mL)	AUC(0–8) (hour)(μg /mL)	MRT (hour)
ME	5 ± 0.01	0.71 ± 0.31	18.63 ± 5.74	26.11 ± 1.1	4.69 ± 0.19
SY	4.67 ± 0.81	1.45 ± 0.62	1.97 ± 0.95	6.93 ± 1.49	4.01 ± 0.26

Abbreviations: AUT, area under the curve; ME, microemulsion with fexofenadine; MRT, mean resistance time; SD, standard deviation; SY, Fexofen^® syrup.

Figure 3 Comparison of the plasma concentration values obtained after administration of FEX loaded microemulsion and Fexofen^®syrup.

Abbreviation: FEX, fexofenadine; w/o, water in oil.