Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate

Figures & data

Table 1 Composition and characterization of MT-loaded niosomal formulations

Code	Ratio (drug:span 60:cholesterol)	Particle size (nm)*	PI*	Zeta potential (mV)*	EE (%)*
N1	1:0.5:1	1,800±67.21	0.721±0.48	−41.8±4.11	25.44±9.7
N2	1:1:1	1,668±114.2	0.752±0.42	−49.6±5.21	34.22±7.5
N3	1:1.5:1	1,254±94.2	0.761±0.29	−56.7±4.95	39.34±5.3
N4	1:2:1	883.7±31.47	0.731±0.34	−64.1±0.95	52.64±6.1**

Notes:

* Mean ± SD (n=3).

** Significant difference (P<0.05) compared to other EE% from other ratios.

Abbreviations: EE, entrapment efficiency; MT, metoprolol tartarate; PI, polydispersity index; SD, standard deviation.

Table 2 Composition of different MT fast dissolving films

Component (mg)	F1	F2	F3	F4	F5	F6
HPMC	100	100	100	0	0	0
MC	0	0	0	200	200	200
PEG400	150	150	150	150	150	150
Saccharine	50	50	50	50	50	50
Menthol	17	17	17	17	17	17
MCC	0	7	14	0	7	14

Note: Contents of each film were casted into PTFE-coated plate (area =28 cm²).

Abbreviations: HPMC, hydroxyl propyl methyl cellulose; MC, methyl cellulose; MCC, microcrystalline cellulose; MT, metoprolol tartarate; PEG, polyethylene glycol.

Table 3 Physical and mechanical properties of MT fast dissolving films

Formulation code	Thickness (mm)*	Weight (mg)*	Surface pH*	Folding endurance (no of folds)*	Drug content (%)*	Disintegration time (seconds)*
F1	0.12±0.003	20.53±1.24	6.8±0.12	230±12	97.98±3.21	180±12
F2	0.14±0.005	20.68±2.34	7.04±0.14	215±20	98.6±1.81	176±18
F3	0.13±0.002	21.48±1.44	6.9±0.21	223±17	99.8±2.32	175±20
F4	0.14±0.003	25.43±3.42	7.1±0.16	219±22	97.6±1.22	89±5.55
F5	0.12±0.004	25.7±1.35	6.82±0.23	235±13	98.5±2.11	64.33±7.85
F6	0.13±0.006	25.53±2.18	7.1±0.18	229±18	99.1±1.61	38.33±7.78**

Notes: Evaluated film is 4 cm² in size, containing 25 mg of the drug.

* Mean ± SD (n≥3).

** Significant lower disintegration time (P<0.05) compared to other values.

Abbreviations: MT, metoprolol tartarate; SD, standard deviation.

Figure 1 DSC thermograms of (1) pure drug (MT), (2) pure polymer (MC), (3) physical mixture (drug and polymer), (4) MT niosomal film, (5) physical mixture (drug and span 60), (6) pure span 60, (7) pure cholesterol, and (8) physical mixture (drug and cholesterol).

Abbreviations: DSC, differential scanning calorimetry; MC, methyl cellulose; MT, metoprolol tartarate.

Figure 2 FTIR spectra of (1) pure drug (MT), (2) pure polymer (MC), (3) physical mixture (drug and polymer), (4) MT niosomal film, (5) physical mixture (drug and cholesterol), (6) physical mixture (drug and span 60), (7) pure cholesterol, and (8) pure span 60.

Abbreviations: FTIR, Fourier transform infrared spectroscopy; MC, methyl cellulose; MT, metoprolol tartarate.

Figure 3 Cumulative MT release from conventional medicated fast dissolving film (F6) in comparison with its niosomal dispersion (N4).

Abbreviation: MT, metoprolol tartarate.

Figure 4 Cumulative MT release from niosomal fast dissolving film (N4F6) in comparison with its niosomal dispersion (N4).

Abbreviation: MT, metoprolol tartarate.

Table 4 Kinetics of MT release from niosomal film and dispersion according to different kinetic models

Formulation	Correlation coefficient (R^2)*				(n)* Korsmeyer–Peppas equation
	Zero order	First order	Higuchi diffusion	Peppas
Niosomal dispersion (N4)	0.9798±0.012	0.9488±0.019	0.9925±0.018	0.9735±0.017	0.481±0.008
Niosomal film (N4F6)	0.9526±0.015	0.91852±0.021	0.9945±0.021	0.9793±0.015	0.476±0.012

Note:

* Mean ± SD (n=3).

Abbreviations: MT, metoprolol tartarate; SD, standard deviation.

Table 5 Physicochemical evaluation of the selected fast dissolving film formulations during stability study

Formula code	Fast dissolving film (F6)			Fast dissolving niosomal film (N4F6)
Time (days)	Zero	60 (room temperature)	60 (40°C)	Zero	60 (room temperature)	60 (40°C)
Weight (mg)*	25.53±2.18	27.53±1.82	26.53±2.68	39.53±3.5	41.23±4.2	42.9±5.3
Surface pH*	7.2±0.15	7.1±0.12	7.2±0.11	6.9±0.2	6.8±0.3	6.9±0.18
Folding endurance(number of folds)*	229±18	225±22	235±16	220±21	221±17	226±23
Disintegration time (seconds)*	38.33±7.78	39.5±5.18	34.33±5.22	40.21±4.78	42.33±3.52	39.53±5.18
Particle size (nm)*	–	–	–	953.4±181.3	972.5±150.8	986.4±191.6
Zeta potential (mV)*	–	–	–	−51±5.30	−48±6.30	−46±4.30

Notes:

* Mean ± SD (n=3). “–” indicates no data.

Abbreviation: SD, standard deviation.

Figure 5 Surface morphology of the selected fast dissolving niosomal film and niosomal dispersion.

Notes: Scanning electron micrograph of (A) niosomal formulation N4 and (B) niosomal fast dissolving film (N4F6).

Figure 6 Plasma concentrations of MT after sublingual and oral administration.

Abbreviation: MT, metoprolol tartarate.

Table 6 Pharmacokinetic parameters of MT in plasma after sublingual administration of fast dissolving niosomal film compared to commercial oral tablets

Formulation	Cmax* (μg mL^−1)	Tmax* (hours)	Ka* (hours^−1)	t½a* (hours)	Kel* (hours^−1)	t½* (hours)	AUC* (μg h mL^−1)	F* (%)
Betaloc^® (MT oral tablet)	1.26±0.223	4.22±0.334	0.24±0.024	2.93±0.022	0.24±0.018	2.93±0.019	10.73±3.48	39.37±11.4
MT niosomal film (N4F6)	2.25±0.086**	2.89±0.26**	0.86±0.16**	0.80±0.15**	0.09±0.018**	7.50±1.47**	31.88±5.09**	91.06±7.18**

Notes:

* Mean ± SD (n=5).

** Significant differences were obtained compared to that of the oral tablets.

Abbreviations: MT, metoprolol tartarate; SD, standard deviation; C_max, maximum concentration; T_max, time of maximum concentration achieved after administration; K_a, absorption rate constant; t_½a, absorption half-life; K_el, elimination rate constant; t_½, elimination half-life; AUC, area under the MT plasma concentration–time curve; F, the absolute bioavailability.