Use of transethosomes for enhancing the transdermal delivery of olmesartan medoxomil: in vitro, ex vivo, and in vivo evaluation

Figures & data

Table 1 Full factorial design (5¹.3¹) used for optimization of TE formulations

Factors (independent variables)	Levels
X1: SAA type	T20, T80, S20, S60, SDC
X2: PC:SAA ratio (w/w)	95:5, 85:15, 75:25
Responses (dependent variables)	Desirability constraints
Y1: EE%	Maximize
Y2: PS (nm)	Minimize
Y3: PDI	Minimize
Y4: ZP (mV)	Maximize (as absolute value)
Y5: Q6h (%)	Maximize

Abbreviations: EE%, entrapment efficiency percentage; PC, phospholipid; PDI, polydispersity index; PS, particle size; Q6h, amount of drug released after 6 hours; S20, Span 20; S60, Span 60; SAA, surfactant; SDC, sodium deoxycholate; T20, Tween 20; T80, Tween 80; TE, transethosome; ZP, zeta potential.

Table 2 Experimental runs, independent variables, and measured response of the 5¹.3¹ full factorial experimental design of OLM-loaded TEs

TE formulation	X1	X2	Y1	Y2	Y3	Y4	Y5
	SAA type	PC:SAA ratio (w/w)	EE%	PS (nm)	PDI	ZP (mV)	Q6h (%)
TE1	T20	95:5	78.91±2.52	324.63±1.26	0.14±0.02	−22.80±0.26	43.18±0.94
TE2	T20	85:15	72.32±0.59	288.81±5.49	0.13±0.06	−11.31±0.37	44.00±0.21
TE3	T20	75:25	63.20±1.15	285.44±2.89	0.14±0.08	−10.21±0.83	56.83±0.48
TE4	T80	95:5	79.71±2.00	380.00±6.00	0.11±0.20	−16.00±0.74	40.85±1.50
TE5	T80	85:15	74.42±1.26	363.75±7.50	0.22±0.09	−15.81±0.51	42.48±0.58
TE6	T80	75:25	68.00±1.46	316.84±7.64	0.06±0.07	−9.00±1.08	53.93±0.24
TE7	S20	95:5	81.80±4.63	394.95±1.80	0.05±0.01	−30.21±0.99	37.98±0.30
TE8	S20	85:15	75.00±1.64	366.71±22.58	0.04±0.02	−19.80±3.14	40.64±0.39
TE9	S20	75:25	67.20±1.01	329.41±2.81	0.24±0.18	−16.50±0.29	43.64±1.20
TE10	S60	95:5	91.90±2.25	442.89±17.64	0.09±0.10	−28.50±0.34	33.95±0.48
TE11	S60	85:15	83.50±3.26	419.35±21.03	0.14±0.03	−17.72±2.80	38.73±3.80
TE12	S60	75:25	71.20±5.35	372.10±19.80	0.12±0.15	−14.91±3.85	39.48±2.50
TE13	SDC	95:5	66.50±1.25	283.90±18.70	0.20±0.12	−35.71±1.63	64.36±2.30
TE14	SDC	85:15	58.54±1.30	222.60±2.59	0.11±0.06	−20.81±0.34	67.44±0.25
TE15	SDC	75:25	48.13±0.80	168.11±1.39	0.13±0.04	−17.82±0.88	69.68±3.00

Note: Data represented as mean ± SD (n=3).

Abbreviations: EE%, entrapment efficiency percentage; OLM, olmesartan medoxomil; PC, phospholipid; PDI, polydispersity index; PS, particle size; Q6h, amount of drug released after 6 hours; S20, Span 20; S60, Span 60; SAA, surfactant; SDC, sodium deoxycholate; T20, Tween 20; T80, Tween 80; TE, transethosome; ZP, zeta potential.

Table 3 Output data of the 51.31 full factorial analysis of TEformulations and predicted and observed values for the optimum TEformula (TE14)

Responses	EE%	PS (nm)	PDI	ZP (mV)	Q6h (%)
Adequate precision	58.87	43.81	4.31	31.76	39.83
Adjusted R^2	0.99	0.98	0.25	0.97	0.98
Predicted R^2	0.98	0.96	−0.53	0.95	0.97
Significant factors	X1, X2	X1, X2	–	X1, X2	X1, X2
Predicted value of optimum formula (TE14)	59.17	223.59	0.10	−20.57	67.72
Observed value of optimum formula (TE14)	58.54	222.60	0.11	−20.81	67.44

Abbreviations: EE%, entrapment efficiency percentage; PDI, polydispersity index; PS, particle size; Q6h, amount of drug released after 6 hours; TE, transethosome; ZP, zeta potential.

Figure 1 Response 3-D plots for the effect of SAA type (X₁) and PC:SAA ratio (X₂) on (A) EE%, (B) PS, (C) PDI, (D) ZP, and (E) Q6h of OLM-loaded TEs.

Abbreviations: 3-D, three-dimensional; EE%, entrapment efficiency percentage; OLM, olmesartan medoxomil; PC, phospholipid; PDI, polydispersity index; PS, particle size; Q6h, amount of drug released after 6 hours; SAA, surfactant; TEs, transethosomes; ZP, zeta potential.

Figure 2 Transmission electron micrograph of the optimum TE formula (TE14).

Abbreviation: TE, transethosome.

Figure 3 DSC thermogram of (A) OLM, (B) PC, (C) SDC, (D) physical mixture of OLM and transethosomal components, and (E) TE14.

Abbreviations: DSC, differential scanning calorimetry; OLM, olmesartan medoxomil; PC, phospholipid; SDC, sodium deoxycholate; TE, transethosome.

Table 4 Effect of storage on the physical properties of TE14

Parameter	TE14 fresh	TE14 after 45 days of storage at 4°C	TE14 after 45 days of storage at 25°C
EE%	58.54±1.30	58.44±1.13	53.94±2.30
PS (nm)	222.60±2.59	222.00±15.00	229.66±35.59
PDI	0.11±0.06	0.14±0.02	0.03±0.01
ZP (mV)	−20.81±0.34	−22.30±3.00	−26.80±1.00
Q6h (%)	67.44±0.25	67.57±0.05	70.42±1.47

Note: Data are presented as mean ± SD (n=3).

Abbreviations: EE%, entrapment efficiency percentage; PDI, polydispersity index; PS, particle size; Q6h, amount of drug released after 6 hours; TE, transethosome; ZP, zeta potential.

Table 5 Ex vivo permeation of OLM suspension, TFs, and TE14 through rat skin and shed snake skin

Formula	Skin type	Total amount of drug permeated per unit area in 12 h (μg/cm^2)	Jmax (μg/cm^2/h)	ER
OLM suspension	Rat skin	123.78±14.02	10.32±1.10	1.00
	Shed snake skin	146.35±8.71	12.19±0.72	1.00
TFs	Rat skin	564.20±0.82	47.01±0.06	3.85
	Shed snake skin	621.25±12.89	51.77±1.07	5.01
TE14	Rat skin	1,154.04±167.74	96.17±13.97	7.88
	Shed snake skin	1,519.68±363.84	126.64±30.32	12.27

Note: Data are presented as mean ± SD (n=3).

Abbreviations: ER, enhancement ratio; J_max, maximum flux; OLM, olmesartan medoxomil; TE, transethosome; TFs, transferosomes.

Figure 4 Cumulative amount of OLM permeated per unit area across excised rat and shed snake skin via TFs and TE14 relative to drug suspension.

Abbreviations: OLM, olmesartan medoxomil; TFs, transferosomes; TE, transethosome.

Figure 5 A tile scan confocal laser scanning microscope photomicrographs of (A) longitudinal section of rat skin treated with 1% FDA solution and (B) fluorolabeled TEs: (a) fluorescence light, (b) transmitted light, and (c) merge between fluorescence light and transmitted light.

Abbreviations: FDA, fluorescein diacetate; TEs, transethosomes.

Figure 6 Photomicrographs showing histopathological sections (H&E stained) of normal untreated rat skin (group I), rat skin treated with OLM suspension (group II), and rat skin treated with TE14 (group III). The magnification power of ×16 (A) to illustrate all skin layers and ×40 (B) to identify the epidermis and dermis, respectively.

Abbreviations: D, dermis; E, epidermis; F, hair follicles; K, keratin; OLM, olmesartan medoxomil; SF, subcutaneous fat; TE, transethosome.

Table 6 Influence of market tablet and TE14 on mean blood pressure in MPA-induced hypertensive rats

Time (hours)	Negative control (mmHg)	HT positive control (mmHg)	Market tablet (mmHg)	TE14 (mmHg)	% reduction in BP by market tablet	% reduction in BP by TE14
0	109.50±3.50	171.00±4.00	177.00±3.26	167.20±4.86	4.00%±2.00%	3.00%±2.00%
1	126.20±1.20	187.50±2.50	138.00±0.81	142.00±29.35	26.00%±0.00%	25.00%±15.00%
2	129.00±1.00	166.50±6.50	127.20±1.83	120.00±6.96	24.00%±1.00%	28.00%±4.00%
4	126.70±2.70	168.00±8.00	128.90±0.83	109.70±19.49	23.00%±1.00%	35.00%±12.00%
6	117.70±4.20	166.00±4.00	126.50±6.94	126.20±4.60	24.00%±4.00%	24.00%±3.00%
8	114.70±1.70	169.50±2.50	140.10±6.40	123.50±12.09	17.00%±4.00%	27.00%±7.00%
24	117.70±0.70	185.50±5.50	165.00±8.16	127.50±4.33	11.00%±4.00%	31.00%±2.00%

Note: Data are presented as mean ± SD (n=6).

Abbreviations: BP, blood pressure; HT, hypertensive; MPA, methyl prednisolone acetate; TE, transethosome.

Figure 7 Dermatokinetic study of TE14 and OLM suspension after topical application.

Abbreviations: OLM, olmesartan medoxomil; TE, transethosome.

ChenMLiuXFahrASkin penetration and deposition of carboxyfluorescein and temoporfin from different lipid vesicular systems: in vitro study with finite and infinite dosage applicationInt J Pharm20114081–222323421316430

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