Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: optimization and in vivo appraisal

Figures & data

Figure 1 Solubility of raloxifene hydrochloride in various oil and surfactant mixtures.

Note: Data expressed as mean ± standard error of mean (n = 3).

Table 1 Emulsification efficiency of various surfactants using different oily phases (1:1)

Surfactant	% transmittance		Time of emulsification (seconds)
	Caproyl 90	Peceol	Caproyl 90	Peceol
Tween 80	93.6	41.8	10	18
Labrasol	66.4	48.2	28	40
Cremophor RH40	99.4	52	3	13
Cremophor EL	99	54	3	15

Table 2 Composition of self-nanoemulsifying nanocarriers constructing phase diagram A (Caproyl 90, Cremophor RH40, and Transcutol)

Formula	Caproyl 90 (%)	Cremophor RH40 (%)	Transcutol (%)	Visual observation
F1	30	70	0	Clear
F2	30	60	10	Clear
F3	30	50	20	Clear
F4	30	40	30	Clear
F5	40	60	0	Clear
F6	40	50	10	Clear
F7	40	40	20	Clear
F8	40	30	30	Clear
F9	50	50	0	Clear
F10	50	40	10	Clear
F11	50	30	20	Clear
F12	60	40	0	Clear
F13	60	30	10	Turbid
F14	70	30	0	Turbid

Table 3 Composition of self-nanoemulsifying nanocarriers constructing phase diagram B (Caproyl 90, Cremophor EL and Transcutol)

Formula	Caproyl 90 (%)	Cremophor EL (%)	Transcutol (%)	Visual observation
P1	30	70	0	Clear
P2	30	60	10	Clear
P3	30	50	20	Clear
P4	30	40	30	Clear
P5	40	60	0	Clear
P6	40	50	10	Clear
P7	40	40	20	Clear
P8	40	30	30	Clear
P9	50	50	0	Clear
P10	50	40	10	Clear
P11	50	30	20	Clear
P12	60	40	0	Turbid
P13	60	30	10	Turbid
P14	70	30	0	Turbid

Figure 2 Ternary phase diagram of system A (Caproyl 90/Cremophor RH40/Transcutol).

Figure 3 Ternary phase diagram of system B (Caproyl 90/Cremophor EL/Transcutol).

Figure 4 Solubility study of raloxifene in selected system ingredients with different triethanolamine ratios.

Note: Data expressed as mean value ± standard error of mean (n = 3).

Table 4 Percentage transmittance of 2% RLX-loaded A-SNEDDS and NA-SNEDDS in different media with different folds of dilution at 638.2 nm

Folds of dilution	% transmittance ± SEMa
	A-SNEDDSb			NA-SNEDDSc
	Distilled water	HCl 0.1 N	Phosphate buffer pH 7.4	Distilled water	HCl 0.1 N	Phosphate buffer pH 7.4
100	95.5 ± 0.33	78 ± 0.60	79.7 ± 0.15	95.4 ± 0.30	85.5 ± 0.35	82.3 ± 0.20
500	96.8 ± 0.25	98.1 ± 0.23	93 ± 0.85	97.9 ± 0.05	97.5 ± 0.25	93 ± 0.50
1000	99.6 ± 0.20	100 ± 0.51	95.6 ± 0.73	99.3 ± 0.35	100 ± 0.15	97.9 ± 0.32

Notes:

a Standard error of mean, n = 3;

b alkalinized self-nanoemulsifying drug-delivery system;

c non-alkalinized self-nanoemulsifying drug-delivery system.

Table 5 Particle size, zeta potential (ZP), polydispersity index (PDI), and pH of selected self-nanoemulsifying formulations

Samples	Particle size	ZP ± SEM (mV)	PDI	pH
	Size ± SEM (d nm)
Placebo NA-SNEDDSa	51.56 ± 0.07	−11.7 ± 1.25	0.106 ± 0.02	6.56
NA-SNEDDS, 0.5%	34.44 ± 0.16	6.76 ± 0.042	0.22 ± 0.003	4.94
NA-SNEDDS, 2%	38.49 ± 4.30	31.7 ± 3.58	0.318 ± 0.22	5.02
Placebo A-SNEDDSb	29.20 ± 0.173	−36.2 ± 2.79	0.190 ± 0.04	8.39
A-SNEDDS, 0.5%	33.79 ± 0.166	−27.2 ± 1.56	0.151 ± 0.01	8.49
A-SNEDDS, 2%	35 ± 2.80	−21.2 ± 3.46	0.28 ± 0.06	8.41

Notes: Data expressed as mean ± standard error of mean (n = 3).

a Nonalkalinized self-nanoemulsifying drug-delivery system loaded with 0.5% w/w raloxifene;

b alkalinized self-nanoemulsifying drug-delivery system loaded with 0.5% w/w raloxifene.

Figure 5 Transmission electron microscopy photograph of nonalkalinized self-nanoemulsifying system with 1000-fold dilution in distilled water (×13,000).

Figure 6 Transmission electron microscopy photograph of alkalinized self-nanoemulsifying system with 1000-folds dilution in distilled water (× 13,000).

Figure 7 Transmission electron microscopy photograph of drug-loaded alkalinized self-nanoemulsifying system with 1000-fold dilution in distilled water (×40,000).

Figure 8 Transmission electron microscopy photograph of placebo nanocarriers with 1000-fold dilution in distilled water (×40,000).

Figure 9 In vitro release of raloxifene aqueous suspension compared to alkalinized and nonalkalinized nanocarriers in 0.1% Tween 80 using dialysis bag method.

Note: Data expressed as mean ± standard error of mean.

Figure 10 In-vitro release of raloxifene aqueous suspension compared to alkalinized (A-SNEDDS) and non-alkalinized (NA-SNEDDS) nanocarriers in 0.1% Tween 80 using dissolution cup method.

Note: Data expressed as mean ± standard error of mean.

Figure 11 Photomicrographs of vaginal smears from female rats at (A) proestrus (nucleated epithelial cells), (B) estrus (cornified cells), (C) metaestrus (leukocytes, cornified, and nucleated epithelial cells), and (D) diestrus phase (leukocytes).

Figure 12 Assessment of raloxifene concentration (μg/mL) in endocrine system (uterus, fallopian tubes, and ovaries) in fed and fasted states from different formulations (suspension, alkalinized, and nonalkalinized self-nanoemulsifying drug-delivery systems) using high-performance liquid chromatography analysis.

Note: Data expressed as mean ± standard error of mean.