Niosomal carriers enhance oral bioavailability of carvedilol: effects of bile salt-enriched vesicles and carrier surface charge

Figures & data

Table 1 Effect of drug concentration, surfactant type, L/D ratio and surfactant to cholesterol molar ratio on entrapment efficiency of carvedilol-loaded niosomes

Surfactant type	Molar ratios		CRV concentration (mg/mL)	L/D (molar ratio)	%EE (mean ± SEM)
	Surfactant	Chol
Span 60	50	50	0.5	20	VNFa
	70	30	0.5	20	32.47±1.93
	70	30	1	20	54.20±2.11
	80	20	0.5	20	58.12±1.65
	80	20	1	10	52.83±1.89
	80	20	1	20	64.76±2.01
	80	20	1	30	84.75±2.70
	80	20	1	40	90.71±2.18
	80	20	2	20	56.08±2.58
	90	10	0.5	20	52.18±2.19
	90	10	1	20	52.79±1.57
	100	0	0.5	20	VNFa
Span 20	80	20	1	20	14.44±0.36
Span 80	80	20	1	20	VNFa

Note:

a Vesicles were not formed.

Abbreviations: Chol, cholesterol; CRV, carvedilol; EE, entrapment efficiency; L/D, lipid-to-drug; SEM, standard error of the mean.

Table 2 The composition, %EE, zeta potential and particle size of bile salt-enriched niosomal formulations

Formulation	Niosome composition (molar ratio)				Symbol	%EE	Zeta potential (mV)	Z-average (nm)	PDI
	Span 60	Chol	Bile salts
			SC	STC
F1 (plain niosome)	80	20	–	–	PN	84.8±2.7	−27.7±3.4	417.4±19.1	0.31±0.02
F2	64	16	20	–	SC20%	89.4±3.9	−54.7±6.9	347.9±10.7	0.35±0.05
F3	56	14	30	–	SC30%	86.2±2.9	−58.5±4.8	441.0±18.1	0.37±0.04
F4	64	16	–	20	STC20%	96.7±1.2	−59.9±3.6	476.9±14.4	0.31 ±0.03
F5	56	14	–	30	STC30%	96.0±2.2	−69.9±2.8	384.4±12.5	0.34±0.03

Note: Data represent the mean ± SEM.

Abbreviations: Chol, cholesterol; EE, entrapment efficiency; PDI, polydispersity index; SC, sodium cholate; SEM, standard error of the mean; STC, sodium taurocholate.

Figure 1 Morphology of plain (F1) (A), bile salt-enriched (F5) (B), cationic (F7) (C), and anionic (F10) (D) carvedilol-loaded niosomes by AFM.

Abbreviation: AFM, atomic force microscopy.

Table 3 The composition, %EE, zeta potential and particle size of niosomal formulations after addition of different charge inducing agents

Formulation	Niosome composition (molar ratio)				Symbol	%EE	Zeta potential (mV)	Z-average (nm)	PDI
	Span 60	Chol	Charge-inducing agents
			CTAB	DCP
F6	76	19	5	–		VNFa	–	–	–
F7	72	18	10	–	CTAB10%	80.1±2.9	+56.0±5.0	496.6±20.6	0.42±0.01
F8	68	17	15	–		92.7±3.8	+72.1±3.3	165.5±1.7	0.18±0.02
F9	76	19	–	5		54.1±2.8	−52.4±2.8	457.9±0.6	0.43±0.05
F10	72	18	–	10	DCP10%	90.1±1.4	−83.5±3.9	379.6±11.4	0.34±0.04

Note: Data is presented as n=3, mean ± SEM.

a Vesicles were not formed.

Abbreviations: Chol, cholesterol; CTAB, hexadecyl-trimethyl ammonium bromide; DCP, dicetyl phosphate; EE, entrapment efficiency; PDI, polydispersity index; SEM, standard error of the mean.

Figure 2 In vitro release profile of carvedilol from the various formulations in SIF containing Tween 80 (A) or in bile salt release medium (B) at 37°C. Data represent the mean ± SEM (n=3).

Notes: SC20%, 20% SC-enriched niosomes; SC30%, 30% SC-enriched niosomes; STC20%, 20% STC enriched niosomes; STC30%, 30% STC enriched niosomes; CTAB10%, cationic niosomes containing 10% CTAB; DCP10%, anionic niosomes containing 10% DCP.

Abbreviations: CTAB, hexadecyl-trimethyl ammonium bromide; DCP, dicetyl phosphate; PN, Plain niosomes; Susp, suspension; F, formulation; SC, sodium cholate; SEM, standard error of the mean; SIF, simulated intestinal fluid; STC, sodium taurocholate.

Figure 3 Mean diameter (A), polydispersity index (B) and zeta potential (C) of different niosomal dispersions before and after 10 hours incubation at 37°C in SIF with bile salts.

Notes: Data represent the mean ± SEM (n=3). SC20%, 20% SC-enriched niosomes; SC30%, 30% SC-enriched niosomes; STC20%, 20% STC enriched niosomes; STC30%, 30% STC enriched niosomes; CTAB10%, cationic niosomes containing 10% CTAB; DCP10%, anionic niosomes containing 10% DCP. *P-value <0.05 vs time 0.

Abbreviations: CTAB, hexadecyl-trimethyl ammonium bromide; DCP, dicetyl phosphate; PDI, polydispersity index; PN, Plain niosomes; F, formulation; SC, sodium cholate; SEM, standard error of the mean; SIF, simulated intestinal fluid; STC, sodium taurocholate.

Table 4 Pharmacokinetic parameters of carvedilol after oral administration of various formulations to male Wistar rats

Formulation	Tmax (h)	Cmax (ng/mL)	AUC0→∞ (ng·h/mL)	FRa (%)	MRT (h)
Suspension (Susp)	0.5±0.1	208.1±6.5	518.0±22.8	–	2.1±0.0
F1 (PN)	0.4±0.0	351.4±42.0	680.7b±37.9	131.4	2.0±0.1
F2 (SC20%)	0.7±0.2	216.5±19.1	951.0c±83.3	183.6	2.9±0.2
F3 (SC30%)	0.7±0.1	240.5±24.6	827.2c±101.1	159.7	3.3±0.3
F4 (STC20%)	0.4±0.0	238.8±29.5	507.5±38.9	98.0	1.8±0.2
F5 (STC30%)	0.5±0.0	360.2±31.3	851.4c±26.1	164.4	2.3±0.2
Susp + empty STC30% niosome	0.6±0.2	327.9±12.2	735.0b±65.3	141.9	1.6±0.1
F7 (CTAB10%)	0.3±0.1	486.5±38.5	890.3c±79.2	171.8	1.9±0.1
F10 (DCP10%)	0.9±0.1	347.5±40.2	998.9c±130.4	192.8	2.6±0.1
Susp + empty DCP niosome	0.5±0.0	301.9±40.1	789.2b±84.8	152.3	2.2±0.0

Notes: Data are presented as n=6, mean ± SEM.

a F_R, The relative bioavailability (%) of carvedilol calculated based on the AUC_0→∞ value of CRV suspension as the reference.

b P-value <0.05 vs suspension.

c P-value <0.05 vs suspension and F1 (PN).

Abbreviations: AUC, area under the drug concentration–time curve; CTAB, hexadecyl-trimethyl ammonium bromide; DCP, dicetyl phosphate; MRT, mean residence time; PN, plain niosomes; SC, sodium cholate; SEM, standard error of the mean; STC, sodium taurocholate.

Figure 4 The mean plasma concentration of carvedilol after a single oral dose (8 mg/kg) of plain (A), bile salt-enriched (B) or charged niosomes (C) compared to carvedilol suspension in rats (n=6, mean ± SEM).

Notes: SC20%, 20% SC-enriched niosomes; SC30%, 30% SC-enriched niosomes; STC20%, 20% STC enriched niosomes; STC30%, 30% STC enriched niosomes; CTAB10%, cationic niosomes containing 10% CTAB; DCP10%, anionic niosomes containing 10% DCP.

Abbreviations: CTAB, hexadecyl-trimethyl ammonium bromide; DCP, dicetyl phosphate; PN, plain niosomes; Susp, suspension; F, formulation; SC, sodium cholate; SEM, standard error of the mean; STC, sodium taurocholate.

Figure 5 The mean plasma concentrations of carvedilol (A) and AUC (B) after oral administration of niosomes to Wistar rats pretreated with cycloheximide (n=6, mean ± SEM) (*P<0.05 vs control).

Notes: SC20%: 20% SC-enriched niosomes; DCP10%: anionic niosomes containing 10% DCP.

Abbreviations: AUC, area under the drug concentration–time curve; F, formulation; DCP, dicetyl phosphate; SC, sodium cholate; SEM, standard error of the mean.

Figure 6 Hematoxylin and eosin staining of small intestinal segments from Wistar rats after oral administration of phosphate buffered saline (A), 20% SC-enriched vesicles (B) and DCP-containing niosomes (C).

Note: Magnification ×100.

Abbreviations: DCP, dicetyl phosphate; SC, sodium cholate.

Figure S1 FTIR spectra of empty niosomes (A), carvedilol-loaded niosomes (B).

Abbreviations: FTIR, Fourier transform infrared; WN, Wavenumber.