A nanohybrid system for taste masking of sildenafil

Figures & data

Figure 1 Chemical structure of sildenafil and its electrospray ionization mass spectrometry/mass spectrometry fragmentations.

Note: *Protonation site.

Figure 2 Powder X-ray diffraction patterns of (A) sildenafil citrate, (B) montmorillonite (MMT), (C) sildenafil–montmorillonite (SDN–MMT), and (D) polyvinylacetal diethylaminoacetate (AEA)-coated SDN–MMT.

Note: *Quartz.

Figure 3 Schematic descriptions for (A) sildenafil–montmorillonite (SDN–MMT) and (B) sildenafil (SDN) molecules drawn by ChemBio3D Ultra 12.0 program (Cambridge Soft, Cambridge, MA).

Notes: carbon, gray; nitrogen, blue; oxygen, red; sulfur, yellow; hydrogen, white.

Figure 4 Thermogravimetric curves of (A) sildenafil citrate, (B) sildenafil– montmorillonite (SDN–MMT), and (C) montmorillonite (MMT).

Table 1 In vitro drug dissolution profiles under a simulated buccal condition

Samples	% drug releasea
	1 minute	2 minutes
Viagra^®	17.17 ± 4.2	48.78 ± 5.49
Sildenafil citrate	53.31 ± 7.47	73.66 ± 4.61
Noncoated nanohybrid	0.00	0.00
AEA-coated nanohybrid	0.66 ± 0.64	4.70 ± 0.53

Notes:

a Values are mean ± SD; n = 3.

Abbreviations: AEA, polyvinylacetal diethylaminoacetate; SD, standard deviation.

Figure 5 Release profiles of sildenafil from (A) sildenafil–montmorillonite (SDN–MMT), (B) polyvinylacetal diethylaminoacetate (AEA)-coated SDN–MMT, (C) Viagra^®, and (D) sildenafil citrate.

Note: The release experiments were performed at pH = 1.2.

Table 2 Pharmacokinetic parameters of SDN after oral administration of Viagra^® and AEA-coated nanohybrids to the beagle dogs

Parameters	Viagra^®a	AEA-coated nanohybrida
AUC0-∞ (μg · hour/mL)	69.2 ± 3.19	78.8 ± 2.32*
Cmax (μg/mL)	10.5 ± 0.641	12.4 ± 0.673*
Tmax (hours)	1.00	2.33 ± 0.577
t1/2 (hours)	5.00 ± 0.074	4.13 ± 0.785
Vd/F (L)	31.3 ± 1.19	22.7 ± 4.49*
Cl/F (L/hour)	4.34 ± 0.205	3.81 ± 0.112*

Notes:

a Values are mean ± SD; n = 3;

* P < 0.05 compared with Viagra^®.

Abbreviations: AEA, polyvinylacetal diethylaminoacetate; AUC_0-∞, area under the plasma concentration-time curve from 0 hours to infinity; Cl/F, total clearance; C_max, maximum plasma concentration; SD, standard deviation; SDN, sildenafil; T_max, time required to reach C_max; t_1/2, elimination half-life; V_d/F, apparent volume of distribution.

Figure 6 Mean plasma concentration–time curves of sildenafil after oral administration of Viagra^® (●) and polyvinylacetal diethylaminoacetate (AEA)-coated hybrid (○) to the beagle dogs.

Table 3 Fraction of nondegraded SDN content in the nanohybrids after incubation under an accelerated stability test condition (40°C, 75% RH)

Time (months)	0	1	2	4	6
SDN–MMT	100.00 (±0.36)	100.06 (±0.41)	102.72 (±0.45)	101.04 (±0.24)	101.75 (±0.19)
AEA-coated SDN–MMT	100.00 (±0.10)	96.53 (±0.23)	101.06 (±0.06)	96.76 (±1.07)	99.35 (±0.34)

Notes: Values are mean ± SD; n = 3 (Unit, %).

Abbreviations: AEA, polyvinylacetal diethylaminoacetate; SD, standard deviation; SDN–MMT, sildenafil–montmorillonite.

Table S1 Accuracy and precision of SDN analyses in plasma samples

SDN (n = 15)	Concentration (ng/mL)		RSD (%)	Accuracy (%)
	Added	Found (mean ± SD)
	Intraday
	5.00	4.73 ± 0.19	3.8	94.6
	50.00	45.87 ± 2.32	4.6	91.7
	150.00	144.32 ± 6.01	4.0	96.2
	Interday
	5.00	4.55 ± 0.22	4.4	91.0
	50.00	46.31 ± 2.20	4.4	92.6
	150.00	140.40 ± 6.82	4.5	93.6

Abbreviations: SD, standard deviation; SDN, sildenafil; RSD, relative standard deviation.

Table S2 Recovery of SDN spiked into plasma samples

SDN (n = 3)	Concentration (ng/mL)		Recovery (%)
	Expected	Found (mean ± SD)
	2.00	1.83 ± 0.13	91.5
	20.00	18.28 ± 1.28	91.4
	100.00	93.62 ± 6.08	93.6

Abbreviations: SD, standard deviation; SDN, sildenafil.

Table S3 In vitro drug dissolution profiles under a simulated buccal and gastric fluid condition

Conditions	% drug releasea
	Viagra^®	Sildenafil citrate	SDN–MMT	AEA-coated SDN–MMT
pH 7.0 (buccal cavity, 2 minutes)	48.78 ± 5.49	73.66 ± 4.61	0.00 ± 0.00	4.70 ± 0.53
pH 1.2 (gastric fluid, 120 minutes)	99.12 ± 2.55	100.11 ± 0.22	2.58 ± 0.26	91.43 ± 0.69

Notes:

a Values are mean ± SD; n = 3.

Abbreviations: AEA, polyvinylacetal diethylaminoacetate; SD, standard deviation; SDN–MMT, sildenafil–montmorillonite.

Table S4 Release profiles of sildenafil from (A) SDN–MMT, (B) AEA-coated SDN–MMT, (C) Viagra^®, and (D) sildenafil citrate. The release experiments were performed at pH = 1.2

Samples	% drug releasea
	10 minutes	20 minutes	40 minutes	60 minutes	90 minutes	120 minutes
(A) SDN–MMT	0.00 (±0.00)	0.00 (±0.00)	0.51 (±0.44)	1.33 (±0.06)	1.92 (±0.34)	2.58 (±0.26)
(B) AEA-coated SDN–MMT	78.40 (±1.10)	84.22 (±0.43)	87.93 (±0.51)	89.36 (±0.71)	90.52 (±0.59)	91.43 (±0.69)
(C) Viagra^®	93.56 (±7.60)	94.03 (±7.21)	95.39 (±5.87)	96.43 (±4.73)	98.00 (±3.42)	99.12 (±2.55)
(D) Sildenafil citrate	97.49 (±1.06)	98.11 (±0.75)	98.33 (±0.30)	99.10 (±0.45)	99.30 (±0.30)	100.11 (±0.22)

Notes:

a Values are mean ± SD; n = 3.

Abbreviations: AEA, polyvinylacetal diethylaminoacetate; SD, standard deviation; SDN–MMT, sildenafil–montmorillonite.

Figure S1 Fourier transform infrared spectra of (A) sildenafil citrate, (B) montmorillonite (MMT), (C) sildenafil–montmorillonite (SDN–MMT), and (D) polyvinylacetal diethylaminoacetate (AEA)-coated SDN–MMT.

Notes: The circles (●) and the dashed vertical lines show the characteristic peaks seen with intact SDN and MMT.

Figure S2 The particle size distribution of (A) sildenafil–montmorillonite (SDN–MMT) and (B) polyvinylacetal diethylaminoacetate (AEA)-coated SDN–MMT.

Figure S3 Typical electrospray ionization mass spectrometry/mass spectrometry spectra of authentic sildenafil.

Figure S4 Representative chromatograms of (A) sildenafil detected in a plasma sample collected for 2 hours after sildenafil administration, and (B) blank plasma sample collected just before sildenafil administration.

Abbreviations: ES, electrospray; MRM, multiple reaction monitoring; TIC, total ion count.