Design and in vitro/in vivo evaluation of sustained-release floating tablets of itopride hydrochloride

Figures & data

Table 1 Formulation of ITO HCl floating tablets

Formula ID number	Content (mg)
	ITO	HPMC 15000	EC	Eudragit RSPM	Avicel	CA	NaHCO3	Magnesium stearate	Total weight
F1	150	100	0	0	60	24.35	10.65	5	350
F2	150	120	0	0	40	24.35	10.65	5	350
F3	150	150	0	0	10	24.35	10.65	5	350
F4	150	0	100	0	60	24.35	10.65	5	350
F5	150	0	120	0	40	24.35	10.65	5	350
F6	150	0	150	0	10	24.35	10.65	5	350
F7	150	0	0	100	60	24.35	10.65	5	350
F8	150	0	0	120	40	24.35	10.65	5	350
F9	150	0	0	150	10	24.35	10.65	5	350
F10	150	0	50	100	10	24.35	10.65	5	350

Abbreviations: ITO, itopride; HCl, hydrochloride; HPMC, hydroxypropyl methylcellulose; EC, ethylcellulose; CA, citric acid.

Table 2 Properties of the prepared tablet

Formula ID number	Mean weight (mg) ± SD, n=20	Mean thickness (mm) ± SD, n=20	Friability (% loss), n=10	Mean hardness (kg) ± SD, n=10	Drug content (mg %) ± SD, n=10
F1	351.7±1.7	3.6±0.029	0.57	7.0±0.77	96.92±2.42
F2	350.8±2.4	3.6±0.035	0.68	7.0±0.62	98.41±2.85
F3	352.3±1.9	3.6±0.017	0.73	6.8±0.77	100.12±1.97
F4	350.6±2.3	3.6±0.011	0.95	4.7±0.69	97.15±2.78
F5	350.5±2.4	3.6±0.004	0.94	4.5±1.04	100.44±2.85
F6	350.8±2.8	3.6±0.021	0.63	5.7±0.85	100.71±3.05
F7	350.7±2.7	3.5±0.024	0.35	7.0±0.65	99.58±1.89
F8	351.6±2.3	3.6±0.009	0.45	6.7±0.87	96.12±1.75
F9	350.5±3.2	3.6±0.001	0.54	7.0±0.67	100.81±2.24
F10	350.1±1.7	3.6±0.009	0.87	7.5±1.67	100.06±1.19

Abbreviation: SD, standard deviation.

Table 3 Floating properties of ITO HCl floating tablets

Formula ID number	Lag time (min)	Floating time (h)	Floating force ± SD (dyne)
F1	2.20	>20	+9.5±0.92
F2	4.38	>20	+8.3±0.65
F3	6.20	>18	+8.8±0.78
F4	No floating occurs	No floating occurs	−1.8±0.04
F5	No floating occurs	No floating occurs	−2.3±0.08
F6	No floating occurs	No floating occurs	−1.6±0.11
F7	3.50	>20	+10.3±0.97
F8	4.12	>20	+9.7±0.85
F9	5.10	>16	+8.4±0.67
F10	20	>12	+7.9±0.59

Abbreviations: ITO, itopride; HCl, hydrochloride; min, minutes; h, hours; SD, standard deviation.

Figure 1 In vitro buoyancy studies.

Figure 2 Dissolution profiles of ITO HCl floating tablets F₁ to F₁₀.

Note: Each value represents an average of three determinations (mean ± SD, n=3).
Abbreviations: ITO, itopride; HCl, hydrochloride; SD, standard deviation; HPMC, hydroxypropyl methylcellulose; EC, ethylcellulose; Eud, eudragit.

Table 4 Kinetic treatment of the dissolution data for ITO HCl floating tablets

Formula ID number	Zero-order			First-order			Higuchi diffusion model
	r	K0	Intercept	r	K1	Intercept	r	Kh	Intercept
F1	0.9292	15.5467	18.8554	−0.9924	−0.2612	2.0678	0.9926	41.7801	0.4592
F2	0.9499	11.6297	21.6025	−0.9559	−0.2720	2.1800	0.9876	37.3064	0.5916
F3	0.8965	7.52021	26.7700	−0.9930	−0.1722	2.0696	0.9776	30.8758	3.2814
F4	0.9351	11.1787	19.5760	−0.9947	−0.1472	1.9902	0.9957	35.4938	0.0230
F5	0.9379	9.18904	16.8818	−0.9915	−0.0908	1.9615	0.9986	30.6651	−0.6809
F6	0.9411	7.42439	17.0139	−0.9917	−0.0787	1.9701	0.9949	24.9661	2.2971
F7	0.9460	6.91069	25.3009	−0.9903	−0.1054	1.9636	0.9920	28.1457	4.1735
F8	0.9519	5.08814	20.1645	−0.9889	−0.0617	1.9780	0.9986	22.9854	1.2258
F9	0.9665	6.19359	8.78054	−0.9934	−0.0442	1.9849	0.9953	20.8059	−3.3245
F10	0.9846	4.29567	4.68339	−0.9780	−0.0318	2.0137	0.9875	17.7194	−8.0137

Notes: Values shown in bold indicate a high value of correlation coefficient for each formula; K₀ = degradation rate constant for zero order; K_I = degradation rate constant for first order; K_h = degradation rate constant for Higuchi model.

Abbreviations: ITO, itopride; HCl, hydrochloride.

Figure 3 Plasma concentrations of ITO HCl after oral administration of the commercial tablets and the prepared ITO HCl sustained-release tablet formula F₁₀.

Abbreviations: ITO, itopride; HCl, hydrochloride.

Table 5 Pharmacokinetic parameters of ITO HCl following oral administration of the prepared ITO HCl sustained-release tablets formula F₁₀ in comparison with the commercial immediate-release tablets, the commercial tablets

Pharmacokinetic parameter	Commercial tablets	Formula (F10)	Significance
Tmax (h)	2	8	S
Cmax (µg/mL)	7.299	5.310	S
Kabs (h^−1)	0.705	0.404	S
t(1/2)ab (h)	0.982	1.712	S
Kel (h^−1)	0.107	0.098	NS
t(1/2)el (h)	6.485	7.014	NS
Vd (L)	1.016	1.069	S
AUC0–24 (µg·h/mL)	47.052	89.356	S
AUC0–∞ (µg·h/mL)	49.894	93.698	S
AUMC0–24 h (µg·h^2/mL)	340.065	1,222.668	S
AUMC(0–∞) (µg·h^2/mL)	436.324	1,422.935	S
MRT (h)	8.745	15.186	S
ClT (mL/min)	5.010	2.668	S
FR (%)	NA	189.910	NA

Abbreviations: ITO, itopride; HCl, hydrochloride; T_max, time for maximum absorption; C_max, maximum (or peak) serum concentration; K_abs, absorption rate constant; t_1/2, half life time of the absorption; K_el, elimination rate constant; V_d, volume of distribution; S, significant; NS, not significant; AUC, area under the curve; AUMC, area under the first moment curve; MRT, mean residence time; Cl_T, total clearance; F_R, relative (or comparative) bioavailability; NA, not applicable.

Table 6 Physical properties of the aged batches of floating tablets after shelf storage for 6 months

Properties	Formula F10
Color change	No changes
Mean weight (mg)	350.01
Mean thickness (mm)	3.6
Friability (% loss)	0.81
Mean hardness (kg)	8.7
Drug content (mg %)	99.42

Figure 4 Effect of aging on the release of ITO HCl from floating tablet formula F₁₀.

Abbreviations: ITO, itopride; HCl, hydrochloride.

Table 7 ITO HCl content in the selected floating tablets stored for 6 months at different temperatures (30°C, 40°C, and 50°C) and at 75% RH

Storage time (months)	Drug remaining (%)
	At 30°C	At 40°C	At 50°C
0	100.15	100.08	100.05
1	100.04	100.02	100.01
2	99.97	99.63	99.44
3	99.62	99.21	98.82
4	99.29	98.81	98.25
5	99.01	98.48	98.03
6	98.82	98.33	97.63
Zero-order
r	−0.991	−0.983	−0.986
A	100.71	100.63	100.59
B	−0.3367	−0.4235	−0.52893
First-order
r	−0.992	−0.984	−0.987
A	2.00308	2.002749	2.00258
B	−14.7×10^−4	−18.5×10^−4	−23.2×10^−4
Mechanism of degradation	First-order	First-order	First-order
K1 (day^−1)	11.25×10^−5	14.20×10^−5	17.80×10^−5

Notes: r is the correlation coefficient, A the intercept, and B the slope of the corresponding rate equation. K₁ is the first-order degradation rate constant. Values shown in bold indicate a high value of correlation coefficient in first-order treatment, indicating that the formula follows first-order kinetics at 30°C, 40°C, and 50°C.

Abbreviations: ITO, itopride; HCl, hydrochloride; RH, relative humidity.

Table 8 First-order degradation kinetics parameters of ITO HCl in different formulae after storage for 6 months at different temperatures

Reciprocal absolute temperature (1/T)	Log first-order degradation rate (K)
1/323*	−3.749
1/313*	−3.847
1/303*	−3.948
A	0.00117092
B	−0.321150
r	−0.999
Predicted K25 (day^−1)	9.32346×10^−5
Shelf life (days) =0.105/K25	1,126.190885
Shelf life (years)	3.077024277

Notes: r is the correlation coefficient, A the intercept, and B the slope of the corresponding equation. K is the first-order degradation rate constant.

Abbreviations: ITO, itopride; HCl, hydrochloride; T, absolute temperature; 1/T, inverse absolute temperature.