Formulation, release characteristics, and bioavailability study of gastroretentive floating matrix tablet and floating raft system of Mebeverine HCl

Figures & data

Table 1 Composition and physical characteristics of MbH floating matrix tablets (mg/tablet)

Formula composition	FT-1	FT-2	FT-3	FT-4	FT-5	FT-6	FT-7	FT-8	FT-9	FT-10	FT-11	FT-12
MbH	200	200	200	200	200	200	200	200	200	200	200	200
HPMC K15M	200	200	200	–	–	–	150	150	150	–	–	–
HPMC K100M	–	–	–	200	200	200	–	–	–	150	150	150
Compitrol 888 ATO5	100	–	–	100	–	–	150	–	–	150	–	–
Precirol ATO5	–	100	–	–	100	–	–	150	–	–	150	–
Glycerol monostearate	–	–	100	–	–	100	–	–	150	–	–	150
NaHCO3	50	50	50	50	50	50	50	50	50	50	50	50
Citric acid	25	25	25	25	25	25	25	25	25	25	25	25
FLt (sec)	34	37	35	40	41	39	28	30	29	34	32	39
Floating duration (h)	>12	>12	>12	>12	>12	>12	>12	>12	>12	>12	>12	>12

Note: All floating matrix tablets contain 2% talc and 2% magnesium stearate as a lubricant.

Abbreviations: FT, floating matrix tablet; MbH, Mebeverine HCl; HPMC, hydroxypropyl methycellulose; FLt, floating lag time.

Table 2 Composition and physical characteristics of sodium alginate-based FRSs containing MbH at 200 mg/10 mL, 1% w/v CaCO₃, and 0.25% w/v sodium citrate

Formulations	FRS-1	FRS-2	FRS-3	FRS-4	FRS-5	FRS-6	FRS-7	FRS-8	FRS-9	FRS-10	FRS-11
Sodium alginate (%w/v)	1	2	3	3	3	3	3	3	3	3	3
HPMC K100M (%)	−	−	−	1	2	2	2	1	1	1	1
Compitrol 888 ATO (%)	−	−	−	−	−	1	−	1	−	2	−
Precirol (%)	−	−	−	−	−	−	1	−	1	−	2
Gelation	–	+	++	++	+++	+++	+++	+++	+++	+++	+++
Floating ability	NF	PF	F	F	F	F	F	F	F	F	F
FLt (sec)	−	25	19	18	24	21	20	19	20	17	15
Floating duration (h)	−	2 h	>12	>12	>12	>12	>12	>12	>12	>12	>12

Notes: (−), no gelation; (+), weak gelation; (++), good gelation; (+++), very good gelation.

Abbreviations: FRS, floating raft system; HPMC, hydroxypropyl methylcellulose; FLt, floating lag time; MbH, Mebeverine HCl.

Figure 1 In vivo study design shows treatment phases.

Abbreviations: FT, floating matrix tablet; FRS, floating raft system.

Figure 2 Gelling and floating ability of FRS-11 (A), FRS-6 (B), and FRS-2 (C).

Abbreviation: FRS, floating raft system.

Figure 3 In vitro dissolution profiles of MbH from HPMC K15M-based FTs in 0.1 N HCl.

Note: Each point represents the mean values of three tablets.
Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose; FT, floating matrix tablet.

Figure 4 In vitro dissolution profiles of MbH from HPMC K100M-based FTs in 0.1 N HCl dissolution media at 37°C.

Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose; FRS, floating raft system.

Figure 5 In vitro dissolution profiles of MbH from alginate-based FRS with different alginate concentrations in 0.1 N HCl dissolution medium at 37°C.

Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose; FT, floating matrix tablet.

Figure 6 In vitro dissolution profiles of MbH from alginate-based FRS with 2% HPMC and different concentrations of lipid polymers in 0.1 N HCl dissolution medium at 37°C.

Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose; FRS, floating raft system.

Figure 7 In vitro dissolution profiles of MbH from alginate-based FRS with 1% HPMC and different concentrations of lipid polymers in 0.1 N HCl dissolution medium at 37°C.

Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose; FRS, floating raft system.

Table 3 Kinetics study of in vitro release data for MbH from selected floating matrix tablets and in situ floating raft systems

Formulation	Zero-order R^2	First-order R^2	Higuchi model R^2	Korsmeyer–Peppas model		Hixson Crowell model R^2
				R^2	n
FT-10	0.851	0.651	0.881	0.988	0.43	0.356
FT-11	0.810	0.714	0.886	0.979	0.59	0.524
FT-12	0.766	0.688	0.897	0.991	0.61	0.635
FRS-10	0.452	0.652	0.958	0.968	0.442	0.599
FRS-11	0.356	0.514	0.979	0.985	0.389	0.412

Notes: R²–regression coefficient; n–release exponent.

Abbreviations: FT, floating matrix tablet; MbH, Mebeverine HCl.

Table 4 Mean pharmacokinetic parameters of MbH obtained after oral administration of Duspatalin^® SR, floating matrix tablet (FT-10), and in situ raft system (FRS-11) to beagle dogs

Parameters	Formulations
	Duspatalin^®	FT-10	FRS-11
AUC0–24h (μg⋅h mL^−1)	68.89±6.36	72.17±8.17	79.92±10.12
AUC0–α (μg⋅h mL^−1)	69.51±6.32	77.69±8.90	91.98±11.13
Cmax (μg·mL^−1)	2.309±0.51	2.306±0.42	2.373±0.15
tmax (h)	3.33±1.0	2.17±1.2	3.0±1.6
Kel	0.149±0.033	0.138±0.034	0.126±0.033
t1/2	4.84±1.1	5.45±1.8	5.85±1.7
F		104.76	116.01

Note: Data presented as mean ± standard deviation (n=6).

Abbreviations: ANOVA, analysis of variance; AUC, area under the curve; C_max, peak plasma concentration; FT, floating matrix tablet; FRS, floating raft system; K_el, elimination rate constant; MbH, Mebeverine HCl; SR, sustained release; t_max, time to reach maximum peak.

Figure 8 Mean plasma concentration–time profiles following oral administration of different formulas of MbH to beagle dogs.

Note: Each point represents mean ± SE (n=6).
Abbreviations: MbH, Mebeverine HCl; FT, floating matrix tablet; FRS, floating raft system; SE, standard error.

Figure 9 HPLC chromatograms of veratic acid and SUL (internal standard) after 10 h of oral administration of FRS-11.

Abbreviations: HPLC, high-performance liquid chromatography; SUL, Sulpiride; FRS, floating raft system; TIC, time incident concentration.

Table 5 ANOVA table of pharmacokinetic parameters following oral administration of single dose of Duspatalin^® SR, FT-10, and FRS-11(200 mg MbH) to six beagle dogs

Statistical test	One-way ANOVA						Independent-samples Kruskal–Wallis test of tmax
Null hypothesis	H0: μcommercial = μFT10 = μFRS11 The alternative hypothesis here is that at least two treatments’ means differ P-value (The significance level is 0.05)						The medians of tmax are the same across different treatments
		Cmax	AUC0–24	AUC0–∞	Kel	t1/2	tmax
Commercial	FT-10	0.993	0.24	0.244	0.591	0.523	0.489
	FRS-11	0.88	0.181	0.152	0.277	0.293
FT-10	Commercial	0.993	0.24	0.244	0.591	0.523
	FRS-11	0.873	0.861	0.77	0.571	0.67
FRS-11	Commercial	0.88	0.181	0.152	0.277	0.293
	FT-10	0.873	0.861	0.77	0.571	0.67

Abbreviations: ANOVA, analysis of variance; AUC, area under the curve; FT, floating matrix tablet; FRS, floating raft system; K_el, elimination rate constant; MbH, Mebeverine HCl; t_max, time to reach maximum peak.