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Open Access Full Text Article ORIGINAL RESEARCH

Formulation, release characteristics, and

bioavailability study of gastroretentive
floating matrix tablet and floating raft
system of Mebeverine HCl

Mohamed A El Nabarawi 1 Abstract: To prolong the residence time of dosage forms within the gastrointestinal tract until
Mahmoud H Teaima 1 all drug is released at the desired rate is one of the real challenges for oral controlled-release
Rehab A Abd El-Monem 2 drug delivery systems. This study was designed to develop a controlled-release floating matrix
Nagla A El Nabarawy 3 tablet and floating raft system of Mebeverine HCl (MbH) and evaluate different excipients for
Dalia A Gaber 4 their floating behavior and in vitro controlled-release profiles. Oral pharmacokinetics of the
optimum matrix tablet, raft system formula, and marketed Duspatalin® 200 mg retard as refer-
1
Department of Pharmaceutics
and Industrial Pharmacy, Faculty of
ence were studied in beagle dogs. The optimized tablet formula (FT-10) and raft system formula
Pharmacy, Cairo University, Cairo, (FRS-11) were found to float within 34 5 sec and 15 7 sec, respectively, and both remain
Egypt; 2Department of Pharmaceutics buoyant over a period of 12 h in simulated gastric fluid. FT-10 (Compritol/HPMC K100M 1:1)
and Industrial Pharmacy, Faculty of
Pharmacy, Misr University for Science showed the slowest drug release among all prepared tablet formulations, releasing about 80.2%
and Technology, 6th of October, of MbH over 8 h. In contrast, FRS-11 (Sodium alginate 3%/HPMC K100M 1%/Precirol 2%)
Egypt; 3National Egyptian Center had the greatest retardation, providing sustained release of 82.1% within 8 h. Compared with
of Environment and Toxicological
Research (NECTER), Faculty of the marketed MbH product, the Cmax of FT-10 was almost the same, while FRS-11 maximum
Medicine, Cairo University, Cairo, concentration was higher. The tmax was 3.33, 2.167, and 3.0 h for marketed MbH product, FT-10,
Egypt; 4Department of Quality
and FRS-11, respectively. In addition, the oral bioavailability experiment showed that the rela-
Control, Holding Company for
Biological Products and Vaccines, tive bioavailability of the MbH was 104.76 and 116.01% after oral administration of FT-10
Cairo, Egypt and FRS-11, respectively, compared to marketed product. These results demonstrated that both
controlled-released floating matrix tablet and raft system would be promising gastroretentive
delivery systems for prolonging drug action.
Keywords: GRDDS, Precirol®, Compritol®, HPMC, Na alginate

Introduction
Oral formulations have earned a significant place among the various dosage forms
due to the ease of administration, patient compliance, and flexibility in formulation.
In most of the cases, the conventional oral delivery systems show limited bioavailability
because of fast gastric emptying time among many other reasons involved.1,2 However,
the recent technological development has resulted in too many novel pharmaceutical
products, mainly the controlled release drug delivery systems to help overcome this
problem. Controlled-release systems aim to maintain the steady plasma level of the
Correspondence: Dalia A Gaber
Department of Quality Control, Holding
drug over a prolonged time period, reduce the adverse side effects, and improve patient
Company for Biological Products and convenience and compliance. Gastroretentive drug delivery system (GRDDS) is one
Vaccines, Cairo 11562, Egypt
Tel 20 100 142 4439
such example where attributes like gastric retention time coupled with the drug release
Email dr_daliaahmed@hotmail.com for extended time have significantly improved patient compliance.3,4

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GRDDS may be achieved by the mechanisms of mucoad- systems.20 Recently, much attention has been focused on the
hesion, flotation, sedimentation, expansion modified shape use of gelucires as carriers in drug delivery systems. The
systems,5–7 or by the simultaneous administration of pharma- gelucires containing only glyceride are used in preparation of
cological agents that delay gastric emptying.8 Floating drug controlled-release formulations. In particular, Compritol 888
delivery systems are those systems having a bulk density ATO5 (Cr), Precirol ATO5 (Pr), and Glycerol monostearate
less than that of the gastric fluids, and thus these systems (GMS) were used as glyceride base for the preparation of
remain buoyant for a prolonged period of time in the stom- controlled-release dosage forms.4
ach without being affected by the gastric emptying rate. The MbH is a musculotropic antispasmodic drug without
drug is released slowly at the desired rate from the system, atropic side effect, whose major therapeutic role is in the
and after release of the drug the residual system is emptied treatment of irritable bowel syndrome. It has a short biologi-
from the stomach.9 Several floating dosage forms have been cal half-life of 2.5 h, plasma protein binding of 75%, and is
launched in the market.10–12 rapidly absorbed after oral administration from the upper
Floating matrix systems appear to be a very attractive part of gastrointestinal tract with peak plasma concentra-
approach in controlled-release system. Floating matrix-type tion occurring in 1–3 h. Hence, MbH has been selected as
formulations are prepared from either swellable hydrophilic a model drug as it fulfills the required pharmacokinetic and
polymers and/or nonswellable lipophilic excipients, like physicochemical properties for controlled delivery.21
waxes and lipids, with carbonate or bicarbonate as the gas- However, to our knowledge, no published data have been
generating agent.13,14 developed for a floating dosage form of MbH and nor has its
In situ gelling technique (also known as raft forming pharmacokinetics been monitored in beagle dogs. Therefore,
system) in combination with carbon dioxide bubble entrap- the present study was undertaken to investigate the efficacy
ment was also reported as another patient compliance design of MbH floating matrix tablet (FT) and floating raft system
for gastroretention. This type of delivery system, initially as (FRS) as a drug delivery system for better control of MbH
a solution form, contains sodium alginate as the in situ gel release using both hydrophilic and lipid polymers in dif-
forming polymer along with carbonates or bicarbonates as ferent ratios. The formulations, with the optimal buoyancy
effervescent agents. When they come in contact with the gas- properties and in vitro drug release, would be selected for
tric fluid, they swell and generate a viscous cohesive gel that a pharmacokinetic study to investigate the in vivo supe-
contains entrapped carbon dioxide bubbles, causing reduction riority over the marketed product “Duspatalin® retard” in
in the density of the systems and contributes to its flotation beagle dogs.
above the gastric content.15 These gels can remain in the
stomach for longer periods of time in comparison to a meal, Materials and method
and this was reported by others.7,16 Hydrophilic polymers are Materials
becoming very popular in formulating oral sustained-release MbH (EIPICO, Mansoura, Egypt), Duspatalin® retard 200 mg
formulations, such as xanthan gum, cellulose derivatives, capsule, (Reference) Batch no T4171, (Abbott Healthcare
alginate sodium, or carbopol.17 Hydroxypropyl methylcel- SAS, Rungis Cedex, France), HPMC with different
lulose (HPMC) is the most commonly and successfully used grades – HPMC K100M and HPMC K15M (El Kahera
hydrophilic material for sustained drug delivery.18 It pos- Pharmaceuticals, Cairo, Egypt), Compritol® 888ATO (glyceryl
sesses some important characteristics including nontoxicity, behenate NF; Gattefossé s.a., Lyon, France), Precirol® ATO5
pH independence, and high water swellability, which con- (glyceryl palmitostearate; Gattefossé s.a.), GMS (Loba
tribute to a desirable drug sustained release profile. In this Chemie Pvt. Ltd., Mumbai, India), sodium alginate LF R5/60
investigation, HPMC was used as a release retardant carrier in (Sisco Research Laboratories Pvt. Ltd., Mumbai, India),
the design of sustained release matrix tablets and raft system sodium citrate, sodium bicarbonate, and calcium carbonate
for Mebeverine HCl (MbH).19 (Adwic Pharmaceuticals, Cairo, Egypt), Acetonitrile
The use of lipid and wax polymers seems to have a high-performance liquid chromatography (HPLC) grade
particular advantage in the preparation of controlled release (Scharlau Chemie SA, Barcelona, Spain), sodium dihydrogen
dosage forms due to their chemical inertness against other phosphate (Koch-Light Laboratories, Colnbrook Bucks, UK),
materials, better characterization of lipid excipients and for- and talc and magnesium stearate were all of pharmaceutical
mulation versatility, and the choice of different drug delivery grade and used as received.

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Dovepress Bioavailability study of floating systems

Method until a homogeneous stable emulsion was obtained. For lip-

Preparation of floating dosage forms id-containing formulations, Cr and Pr were melted in a water
of MbH bath adjusted to a 90 C temperature and then MbH was dis-
Preparation of FT of MbH persed in the molten lipid (200 mg/10 mL formulation). A cal-
Twelve floating tablets formulations, each containing 200 mg of culated volume of the in situ gelling sol, containing sodium
MbH, were prepared by a direct compression method. Briefly, citrate 0.25% w/v and HPMC solution, was heated to the same
200 mg of the drug, polymer, and other additives as mentioned temperature of molten lipid and then added to MbH lipid dis-
in Table 1 were mixed in incremental amounts, and then the persion. Carbonate was then added (1% w/v) to the prepared
mixture was screened through a 40-mesh sieve (425 m). emulsion and mixed well (as mentioned earlier).23,24
Magnesium stearate and purified talc were then added. Powder
mixtures were compressed into tablets using a single-punch
In vitro evaluation of physicochemical
tablet compression machine (Cadmach, Ahmedabad, India) characteristics of MbH FT and FRS
fit with 10 mm concave-faced punches. Compression was Evaluation of the precompression and
controlled to produce a 5-kg/cm2 tablet-crushing strength.22 postcompression parameters of FT of MbH
Angle of repose, compressibility index, and Hausner’s ratio
of powder mixture were measured.25 Compressed tablets were
Preparation of FRS of MbH
characterized for weight variation, crushing strength, diameter,
Eleven liquid formulations with in situ gelling and floating
thickness, friability, and uniformity of drug content.26,27
properties were prepared. The formulations were liquid sols
of alginate containing calcium carbonate as an effervescent
agent. Different concentrations of HPMC K100M, Cr, and
In vitro gelation study of FRS of MbH
Gelation capacity was determined by placing 1 mL of the
Pr were incorporated into alginate-based formulations to
formulation in a test tube containing 5 mL of gelation medium
retard the drug release rate. Composition of the prepared
(simulated gastric fluid pH 1.2). All were freshly prepared
FRS is shown in Table 2. Calculated amounts of sodium
and equilibrated at 37 C and were added slowly. Gelation
alginate and HPMC were individually dispersed in deion-
was observed by visual examination.2
ized water, and then sodium citrate 0.25% w/v was added
to sodium alginate solution and heated to 90 C with stirring
till a homogeneous viscous liquid was obtained; then MbH In vitro floating study
was dispersed (200 mg/10 mL formulation) in the viscous The in vitro buoyancy was determined by investigation of
liquid. Carbonate dispersion providing 1% w/v concentra- floating lag time (FLt) and floating duration for all formula-
tion was then added to the prepared emulsion and mixed tions. The test was performed by placing each of the tablets
well with a homogenizer (Homogenizer T-25; IKA, Staufen, or 10 mL raft systems (placed into watch glass) in a 250 mL
Germany) at a speed of 2,000 rpm for a duration of 10 min beaker containing 200 mL of 0.1 N HCl (pH 1.2), and the

Table 1 Composition and physical characteristics of MbH floating matrix tablets (mg/tablet)
Formula FT-1 FT-2 FT-3 FT-4 FT-5 FT-6 FT-7 FT-8 FT-9 FT-10 FT-11 FT-12
composition
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.

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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) – 2h 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.

system was maintained at 37 C 0.5 C in a water bath. Their In vivo pharmacokinetic study in
physical state was observed for 12 h. The time between intro- beagle dogs
duction of the dosage form and its buoyancy on the 0.1 N HCl An in vivo pharmacokinetic study was conducted in accor-
(FLt) and the time during which the dosage form remains dance with the ethical guidelines for investigations in labora-
floating (duration of floating) were noted. Three replicate tory animals and was approved by the Institutional Animal
measurements for each formula were performed.22 Ethics Committee, Faculty of Pharmacy, Cairo University,
(number [PI/1535]). All procedures and care of the beagle
Measurement of in vitro MbH release dogs were in accordance with institutional guidelines for
The release of MbH from FT and FRS was determined using animal use in research. Six male beagle dogs weighing
USP dissolution test apparatus II (USP 24). The temperature 11–14.5 kg were used and divided into three groups randomly
was maintained at 37 C with a paddle stirrer at 50 rpm. The (Figure 1), and the study was carried out in a crossover
dissolution medium used was 900 mL of 0.1 N HCl (pH 1.2). experimental design in three phases with a washout period
One FT of MbH or 10 mL of FRS (placed into watch glass) of 1 week to eliminate the effect of the prior dose before
was kept in the dissolution vessel without much disturbance. the next drug administration. All dogs were fasted over-
At each predetermined time interval, a precisely measured night prior to the experiment; no food was allowed until a
sample of the dissolution medium was removed and replen- standard meal was served 2 h after dosing. Water was avail-
ished with the same volume of a prewarmed (37 C) fresh able ad libitum throughout the study period. During each
medium. Absorbance of Mebeverin in withdrawn samples period, dogs received orally the following formulations:
was measured at 362 nm using a UV spectrophotometer FT-10 (one floating tablet), FRS-11 (10 mL equivalent to
(UV-1601; Shimadzu, Kyoto, Japan). All dissolution runs
were performed in triplicate.2

Mechanism and kinetics of drug release

Drug release data were analyzed according to zero-order,
first-order, Higuchi, Hixon–Crowell, Peppas, and Weibull
kinetic equations.28 DDSolver, which is an add-in program
for Microsoft Excel for modeling and comparison of drug
release profiles was used. The model with the highest
coefficient of determination (R2) was considered to be the
best fitting one.29

Statistical analysis
Results were analyzed by using the software SPSS 17.0
(SPSS Inc., Chicago, IL, USA) applying one-way analysis
of variance (ANOVA) and paired Student’s t-test. Differ-
ences between formulations were considered to be significant
Figure 1 In vivo study design shows treatment phases.
at P 0.05. Abbreviations: FT, floating matrix tablet; FRS, floating raft system.

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Dovepress Bioavailability study of floating systems

200 mg of MbH), and one sustained-release MbH marketed concentrations of veratic acid are presented as the mean
product “Duspatalin® retard 200 mg” capsule. Five milliliter standard deviation. The peak plasma concentration (Cmax),
of blood samples were taken into a heparinized blood col- the time to reach the maximum peak (tmax), and the time the
lection tube via a detaining needle at predose and at 0.5, 1, veratic acid first appeared in the plasma (tlag) were obtained as
2, 3, 4, 6, 8, 12, and 24 h postdose. The plasma fraction was directly measured values. The terminal elimination rate con-
obtained by centrifuging the samples at 3,500 rpm for 10 min, stant (Kel) was estimated by linear regression analysis of the
and this was stored at 20 C until analysis. The plasma con- terminal portion of the log-linear plasma concentration–time
centration was assayed using HPLC.30 profile of veratic acid. The extent of absorption (AUC0–t) was
calculated using linear trapezoidal rules. Extrapolated AUCs
Chromatographic system (AUC0– ) were determined by the following equation:
Drug concentrations in plasma were determined by a previ-
ously reported HPLC method.31 The method allowed the AUC0– AUC0–t Ct/Kel (1)
determination of Mebeverine metabolite (veratic acid) using
Sulpiride (SUL) as internal standard. The analysis was carried The Wagner–Nelson model was used to calculate the
out on a Waters Acquity HPLC™ (Waters Corp., Milford, percentage of Mebeverine dose-absorbed profiles.33
MA, USA). The separation of these compounds was achieved
on a Waters® C18 column (250 mm, 4.6 mm i.d., 5 m particle Fat (Ct Kel AUC0–t) 1/Kel AUC0– , (2)
size) using isocratic mobile phase containing a mixture of
acetonitrile and 0.01 M dihydrogen phosphate buffer 45:55 where Fat is the fraction of drug absorbed at time t, Ct is the
(v/v). The analysis was performed at pH 4, flow rate of concentration of drug in the plasma at time t, and Kel is the
1 mL min 1, and with fluorescence detection at excitation elimination rate constant. The elimination rate constant, Kel,
300 nm and emission 365 nm. Prior to any analysis, the was calculated from the mean plasma concentration–time
mobile phase was filtered using 0.45 m filters. The system profile of MbH.33
was equilibrated with the mobile phase before injection. All The relative bioavailability values (F) were calculated
determinations were made at ambient temperature. using the following formula with the market product as a
All data were collected and analyzed using Lynx TMV 4.1 reference.
software (Waters Corp.). The method was validated for selec-
tivity, linearity, precision, accuracy, carryover, extraction F AUCtest/AUCref 100 (3)
recovery, and stability, briefly before the beginning of this
study, according to a previously published assay study.31 Statistical evaluation of the results
The in vivo experiment was preplanned to compare the differ-
Drug analysis ence between the mean pharmacokinetic parameters obtained
Mebeverine metabolite (veratic acid) concentrations in after administration of each of the three treatments into each
plasma were measured using a validated specific and sen- group of dogs in a crossover model. All statistical differences
sitive HPLC method. Briefly, sample aliquots of 200 L in data were evaluated by IBM SPSS Statistics 20 (Armonk,
were added to a 1.8 mL Eppendorf tube and were spiked NY, USA) using one-way ANOVA with extended LSD post
with 20 L of SUL, the internal standard. The mixture was hoc test for the determined pharmacokinetic parameters,
vortexed (Paramix II; Julabo, Seelbach, Germany) for 30 sec, and P-value 0.05 was considered significant. Nonpara-
and then 800 L of acetonitrile was added and the mixture metric Kruskal–Wallis test was done to compare the data of
was vortexed for 1 min and centrifuged at 20,000 rpm for tmax obtained from different treatments.
15 min at 10 C. The supernatant was transferred into a clean
glass tube and evaporated to dryness under a gentle stream Results and discussion
of nitrogen. The residue was reconstituted in 200 L HPLC Assessment of FT and FRS for delivery
eluent, vortexed for 1 min, and 20 L of this was injected of MbH
into the HPLC system.31,32 Powder mixture characterization and
physicochemical characters of FT of MbH
Calculation of MbH parameters and statistical analysis The FTs were prepared by a single compression method. To
Pharmacokinetic parameters were estimated from the indi- extend the drug residence time in the stomach, the tablets
vidual plasma concentrations versus time profiles. Plasma with a density lower than the gastric fluids were developed by

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incorporating a CO2-generating agent (sodium bicarbonate). superior to monovalent cations in promoting the gelation of
One of the following lipid polymers (Cr/Pr/GMS) with the polysaccharide. In the present study, CaCO3 was used as
HPMC K15M or HPMC K100M were used in different ratios a source of calcium, and also as a gas-generating agent. Upon
as sustained release agents and entrapped the produced gas to contact of the formulation with acidic pH of the stomach,
maintain buoyant capacities. The details of the formulations the dispersed CaCO3 dissolves and releases carbon dioxide
are depicted in Table 1. and enhances the gel buoyancy.
All formulation components powders were free flowing.
The angle of repose of the powder mixture for all formula- Gelling properties of FRS of MbH
tions (FT-1–FT-12) was 29 C, indicating excellent flow The gelling properties of raft systems are of importance for
properties. Hausner’s ratios and compressibility indices their proposed oral administration. The concentration of the
ranged from 1.2 to 1.27 and 8.52% to 11.15%, respectively. gelling polymer should be sufficiently high for the formation
The results of flow properties are acceptable for all powder of gels of satisfactory gel strength for use as a delivery vehicle
mixtures; data not shown.34 and sufficiently low to maintain an acceptable viscosity for
Floating tablets were whitish-buff or white in color, all ease of swallowing.
were round, concave, with smooth surface on both sides, Calcium carbonate being present in the formulation as
and no visible cracks were observed. The mean diameter insoluble dispersion releases calcium ions in acidic media,
of floating tablets was 10.0 0.0 mm, while mean thickness which combine with the polymer sol, causing gelation of the
ranged from 3.2 to 3.4 mm. Mean hardness was in the range FRS.39 Studies reported that sodium bicarbonate is preferred
of 4–6 kg/cm2, indicating that the floating tablets are of as the gas-generating agent and that CaCO3 showed internal
sufficient strength to withstand physical abrasion.35 The ionotropic gelation during storage.2 Thus, in our study, sodium
percentage friability for all formulations was less than 1%, citrate was added to prevent premature gelation which may
which is an indication of satisfactory mechanical resistance. occur during storage, as sodium citrate complexes the free Ca2
All the formulated products lay within the pharmacopoeial ions and only releases them in the acidic environment of the
requirement of 5% for weight variation. The percentage of stomach. The formulation thus remains in liquid form until
mean drug content ranged from 98.6% to 100.5%, which met it reaches the stomach, where gelation is instantaneous. The
the pharmacopeial standard.36 optimum amount of sodium citrate that maintained fluidity
of the formulation before administration and then gelation
Physicochemical characters of FRS of MbH after administering the formulation has been previously
The compositions of the eleven formulations investigated are reported.23,39 HPMC K100 M was incorporated to improve the
presented in Table 2. A visual estimation of the formulations gelation capacity of alginate, and as sustained-release materials
indicated that they were fluid upon preparation and would amphiphilic lipids (Cr, Pr) were incorporated into alginate-
not cause any issue for swallowing. Low-molecular-weight based formulations to increase retardation of drug release.
alginate LFR5/60 used in this study produced gels with larger The gelation study was conducted in 0.1 N HCl, pH 1.2
volume and thickness than other alginates.37 (simulated gastric fluid [SGF]). All the formulations except
To meet the expected floating requirements, in situ FRS-1 showed rapid gelation when in contact with the SGF.
formed raft system should preserve its integrity without dis- Increasing the alginate concentration from 1% to 3% increased
solving or eroding, while floating for a prolonged period to the gelation capacity as the gelation time decreased and gel
facilitate sustained release of drugs. In the presence of either strength increased. Formulations with low content of sodium
divalent or monovalent cations in the medium, sol to gel alginate (FRS-1 and FRS-2) formed weak gels, leaving turbid
transformation of alginate occurs; the mechanism involved solutions below that dissolved rapidly within 2 and 4 h, respec-
in sol to gel transition by these polymers has been reported tively. Such systems are not suitable as oral liquid formula-
by many authors.38 In an ion-free aqueous medium, sodium tions as they will be removed earlier from the stomach by the
alginate forms double helices, and the helices are only weakly peristaltic movements.24 FRS-3 with a higher concentration of
associated with each other by van der Waals attraction and the alginate forms a rigid gel in short gelation time. Results also
solution has low viscosity. When gel-promoting cations are showed that incorporation of HPMC in the system resulted in
present, some of the helices associate into cation-mediated adequate gel strength when pressed with a pair of fine forceps,
aggregates, which cross-link the polymer. Tang et al’s indicating that formed gel will withstand the shear forces
study,15 reported that divalent ions such as calcium are likely to be encountered in the stomach. As shown in Table 2,

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Dovepress Bioavailability study of floating systems

incorporation of lipids in raft system did not show significant be released and entrapped in formed gel network producing
change in gelation capacity. buoyant formulation.41 An increase in alginate concentra-
tion resulted in decreasing FLt and an increase in floating
In vitro floating properties duration of the prepared systems.42 Using HPMC in con-
In vitro floating properties of FTs centration 1 and 2% (FRS-4, FRS-5) showed no significant
The floating ability of the prepared formulations was evalu- effect (P 0.05) on FLt or duration. Increasing lipid polymer
ated in SGF (Figure 2). Faster onset and continuous flotation content enhanced the floating ability, where a decrease in FLt
can prevent the dosage forms from premature evacuation was achieved in FRS-10 and FRS-11 (Table 2). This enhance-
from the stomach. Thus, an investigation into the floating ment in floating ability was attributed to the low density of
properties of the dosage form in vitro would help to develop the used lipids in addition to the three-dimensional network
an optimized drug product with the desired characteristics. of the cubic phase of the used lipids, which further reduces
The time the formulation took to emerge on the medium the permeability of the formed gel, leading to a reduction in
surface (FLt) and the time the formulation constantly floated diffusion of the entrapped carbon dioxide, thus resulting in
on the dissolution medium surface (duration of floating) were excellent buoyancy.43
evaluated and are shown in Table 1. Sodium bicarbonate
(NaHCO3) and citric acid were used in the ratio of 2:1 as a gas In vitro release study
forming mixture.40 Citric acid was added to negate the effect In vitro release study of FTs
of difference in acidity in vivo. Sodium bicarbonate generates In vitro drug release experiments were done to investigate
CO2 in the presence of dissolution medium (0.1 N HCl). The the probability of employing HPMC K15M and HPMC
gas generated is trapped and protected within the gel formed K100M as matrix for intragastric floating drug delivery and
by hydration of the polymer, thus decreasing the density of also to evaluate the effect of using Cr, Pr, and GMS in two
the tablet, and so the tablet becomes buoyant. different ratios on the retardation of drug release. The in vitro
As can be seen from Table 1, all tablets could float for dissolution profiles of MbH from FTs in 0.1N HCl for 8 h
more than 12 h, but their FLt was different. The result are shown in Figures 3–7. Release profiles are plotting the
indicated that CO2 bubbles generated could be entrapped percent cumulative amount of drug released in 0.1 N HCl
efficiently in the polymer gel layers. HPMC used a sustained- against time. Floating tablets formulations (FT-1–FT-12) kept
release material, and its density became lower when the their integrity throughout the release studies, with a slow
polymer was swelling in the fluid.41 Results showed that FLt diminution of the matrix thickness due to polymer dissolu-
ranged between 32 and 41 sec, and an increase was observed tion. It was observed that polymers in the matrix undergo
in FLt with the increase in HPMC viscosity, suggesting that simultaneous swelling, dissolution, and diffusion into the
the hydration and the gas forming process of the tablet pro- bulk medium, resulting in erosion and reduction of the matrix
longed, but it was not significant at P 0.5. Incorporation of strength. It is also considered that the gas bubbles dissipating
lipid polymer showed no significant difference (P 0.5) in
FLt or floating duration between different formulations.

In vitro floating properties of FRS

In our study calcium carbonate was used as gas forming
agent, in the acidic medium of stomach carbon dioxide will

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.
Figure 2 Gelling and floating ability of FRS-11 (A), FRS-6 (B), and FRS-2 (C). Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose;
Abbreviation: FRS, floating raft system. FT, floating matrix tablet.

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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.
Figure 4 In vitro dissolution profiles of MbH from HPMC K100M-based FTs in 0.1 Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose;
N HCl dissolution media at 37 C. FRS, floating raft system.
Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose;
FT, floating matrix tablet.

significant decrease in the drug release (P 0.5) in the acidic

from the inside to the outside of the matrix debilitate the medium owing to the formation of a hydrophobic insoluble
matrix structure.44 The reduction in HPMC K15M-based FT mass that acts as a barrier to drug diffusion,46 and consequently
size was greater than that in HPMC K100M FTs. the initial burst effect and release rate were decreased. The
Figure 3 shows the release profiles of MbH from the results showed that the release of MbH from the prepared
HPMC K15M-based floating matrix. FT-1, FT-2, and FT-3 formulations was in the following order FT-3 FT-1 FT-2
exhibited burst release since about 23%, 28%, and 32% FT-9 FT-8 FT-7. The slower MbH release rate with the
of MbH released in 30 min, respectively. The initial burst decreased HPMC content could be due to slower penetration
effect could be due to rapid dissolution of the drug from the of water into the matrix and/or more matrix erosion in addition
surface while the HPMC K15M undergoes hydration to form to the increase in hydrophobic mass. This may be explained
a protective gel layer.45 T50 (time required to release 50% by an axial expansion of the tablets.47 Close examination of
of the drug) was 2.1 h, 1.1 h, and 1.00 h for FT-1, FT-2, and tablets showed that the extent of their deformation was greater
FT-3, respectively, and almost 100% of the drug was released for those of higher HPMC content. That drug dissolution
within 4 h. So, F1, F-2, and F-3 did not show the expected makes more pores in matrix structure facilitated the penetra-
sustained release characteristics, whereas, formulas F7, F8, tion of water into the matrix interior, promoting diffusion of
and F9 containing higher lipid polymer ratio released 20%, more drug from the tablets. This might be the main reason
24%, and 30% of MbH, respectively, in 30 min. The decrease why decreasing HPMC content in tablets prolonged drug
in HPMC content with the accompanying increase in lipid dissolution significantly and thus met our design objectives.
polymer content in the matrix tablets (FT-7, FT-8) lead to a The difference in release between Cr, Pr, and GMS tablets

Figure 7 In vitro dissolution profiles of MbH from alginate-based FRS with 1%

Figure 5 In vitro dissolution profiles of MbH from alginate-based FRS with different HPMC and different concentrations of lipid polymers in 0.1 N HCl dissolution
alginate concentrations in 0.1 N HCl dissolution medium at 37 C. medium at 37 C.
Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose; Abbreviations: MbH, Mebeverine HCl; HPMC, hydroxypropyl methylcellulose;
FRS, floating raft system. FRS, floating raft system.

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Dovepress Bioavailability study of floating systems

could be interpreted as a result of the Hydrophile-Lipophile Xiaochen et al50 reported that combined use of lipid-based
Balance (HLB) value of the lipid polymers. GMS, the one with Cr and hydrophilic Methocel sustained the highly soluble
higher HLB value of 3.8, had less capability for sustaining pseudoephedrine release significantly compared to any for-
drug release, compared to Pr and Cr, which had lower HLB mulation that was composed of only single matrix excipients.
values of 2. Lipids with lower HLB value readily transform Considering the floating behavior together with the release
from the lamellar phase to the cubic phase, which is one main pattern, FT-10 was considered as the optimum formulation.
cause for sustaining drug release.48 The matrix of this formulation was used to further investigate
Replacing HPMC K15M with HPMC K100M with the in vivo pharmacokinetic parameters in beagle dogs.
same ratio resulted in FT-4, 5, and 6 and FT-10, 11, and 12
that produced significantly (P 0.05) lower release rate In vitro release study from raft system
compared to HPMC K15M based tablets (Figure 4). It can In this study, FRSs with different combinations of sodium
be suggested that the relative higher viscosity of the polymer alginate with HPMC K100 M and lipid polymers (Cr and Pr)
can lead to formation of more viscous matrix, which provides were prepared. Sodium alginate was used in three different
greater diffusional resistance compared to that in the case concentrations: 1, 2, and 3% w/v. HPMC K100 was used in
of the less viscous polymer. A similar explanation was also 1% and 2% concentrations, while Cr and Pr were used at two
reported by others.49 levels, 1 and 2%, to prepare eleven floating raft formulations
Concerning FT4, FT-5, and FT-6 release profiles, it was (FRS-1–FRS-11). The release of the drug from the alginate
observed that the rate of drug release was different; 50% of FRS is shown in Figure 5. A significant decrease (P 0.05)
the drug was released after 4.0 h, 2.7 h, and 2 h from FT-4, in the rate and extent of drug release was observed with the
FT-5, and FT-6, respectively, that could be explained on increase in alginate concentration from 1 to 3%, which could
the basis of HLB values of lipid polymers (as previously be attributed on the basis of polymer matrix density and the
discussed). increase in the diffusional path length the drug molecules
The in vitro release profiles of FT-10, FT-11, and FT-12 have to traverse with increasing polymer concentration.
are shown in Figure 4. As can be seen from the Figure, Preparations formed of alginate and HPMC K100M (FRS-4
GMS-based FT (FT-12) showed the highest release rate and FRS-5) did not show significant retardation in drug
(t50, 2.9 h and t85,4 h), while the Cr-based one showed release when compared with FRS-3. T50, T85 were (1.0 h,
the slowest release (t50, 5.2 h and t85, 8 h). The release of 3 h), (1.2 h, 3.2 h), and (1.1 h, 3.5 h) for FRS-3, FRS-4, and
MbH was in the following order FT-12 FT-11 FT-10. FRS-5, respectively, which could be interpreted on the basis
The faster release rate from FT-11 as compared with FT-10 of the hydrophilic nature of both alginate and HPMC and
could be explained on the basis of melting temperature of the fact that the matrix formed was not able to produce the
both polymers, and also because Cr has higher melting range intended retardation.
than Pr and because greater loss of structure and weakening Figures 6 and 7 show the effect of Cr and Pr incorpora-
of bonds between particles at 37 C occur during compression tion at two levels in alginate FRS on MbH release. FRS-6
of Pr-based matrices. Our study showed that combined use and FRS-7 release profiles showed significant retardation
of lipid-based polymer and HPMC K100M sustained drug (P 0.5) in MbH release as compared with FRS-5, which
release significantly. Hydrophilic polymers such as HPMC proved that the use of lipid polymers significantly decreased
K100M rely on water absorption to produce gel swelling the rate and extent of drug release. Studies reported that when
and matrix relaxation, which subsequently facilitate drug polar amphiphilic lipids placed in gastric fluids reorganize
dissolution and diffusion from the matrix. When a lipid- into lipid bilayers forming a reversed micellar phase, the
based excipient is concurrently present in the same matrix, its cubic phase as the dominate phase. The stiffness and high
lipophilicity is able to reduce water uptake rate by the matrix. viscosity of the cubic phase can provide a slow sustained
Consequently, drug dissolution and diffusion from the tablet release of the incorporated drug by slowing its diffusion.43
matrix is reduced to produce a sustained release pattern for Pr exhibited more pronounced effect on both rate and
a prolonged period of time. Tiwari and Rajabi-Siahboomi45 extent of MbH release, which could be explained based
found that combined use of hydrophilic and hydrophobic on viscosity of the polymer. Although both Cr and Pr are
excipients was not desirable because immediate tablet disin- polar amphiphilic lipid polymers and both have the ability
tegration and drug dissolution took place. We did not observe to control drug release through formation of cubic structure,
such phenomena in our dissolution studies. Another study by the higher drug release rate obtained from Cr- compared to

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El Nabarawi et al Dovepress

Pr-based formulation is attributed to its lower viscosity and mechanism and that drug release was governed by both dif-
incomplete transformation to cubic phase gel.51 fusion and matrix erosion,53 whereas, the value of n in the
Use of 1% of Cr and Pr while decreasing HPMC to 1% in case of FT-10 (n 0.43) revealed a Fickian diffusion release
FRS-8 and FRS-9 showed better control of drug release, which mechanism of MbH from this FT.
could be interpreted on the basis of rapid hydration of HPMC The regression coefficient (R2) of FRSs FRS-10 and
and more rapid penetration of water into the matrix with FRS-11 indicated that the Peppas power law equation had
faster release rate of MbH. Moreover, by increasing Cr to 2% the best fit to the experimental data for both formulations
(FRS-10), the rate of drug release decreased, but this decrease evaluated. The values for the release exponent (n) were 0.44
was not significant at P 0.05 when compared to FRS-8, and 0.39 for FRS-10 and FRS-11, respectively, indicating that
while the retardation of drug release was significant when Pr the mechanism of MbH release from the gels is controlled by
content increased from 1% (FRS-9) to 2% (FRS-11). Results Fickian diffusion and that the release rate of MbH from these
also revealed that the release from FRS-11 is significantly systems is controlled by diffusion through channels within
slower than release from FRS-10 (P 0.5), which could be the structure of the hydrogels. These results are in agreement
explained on the basis of lipid viscosity as mentioned earlier. with the kinetic model reported by Rao and Shelar.54 Abou
Our investigation showed that dissolution of MbH was well Youssef et al2 reported the same results regarding the release
prolonged to a large extent with the use of hydrophilic matrix of metronidazole from sodium alginate and gelan gum in in
HPMC K100M with lipophilic polymer (Pr). In addition, situ gelling systems.
the increase in Pr concentration with the decrease of HPMC
content produced a sustained-release pattern for a prolonged Pharmacokinetic study
period of time. Based on these results, FRS-11 was used for A pharmacokinetic study of the optimized FT (FT-10) and in
further investigation in beagle dogs. situ raft system (FRS-11) of MbH compared with marketed
MbH product (Duspitaline® retard 200 mg) was done fol-
Kinetics of release lowing oral administration of 200 mg of the drug in beagle
In order to investigate the release kinetics of MbH from dogs in three phases. The mean concentration–time profiles
FT and FRS, the data of in vitro release experiments of for the FT (FT-10), FRS (FRS-11), and commercial product
optimum formulations were treated according to the model- are shown in Figure 8. The pharmacokinetic parameters are
dependent methods, zero order, first order, Higuchi model, shown in Table 4. Studies showed that after oral administra-
Korsmeyer–Peppas model, and Hixson–Crowell model tion of MbH, only traces of Mebeverine were found in plasma
(Table 3). The criteria for selecting the most appropriate with simultaneous appearance of veratic acid; hence, veratic
model was based on best fit indicated by the value of coef- acid concentrations in plasma were determined for monitor-
ficient of determination (R2) nearer to 1.52 Concerning FT-10, ing the therapeutic efficacy of MbH. HPLC chromatograms
FT-11, and FT-12, the highest values of R2 were obtained of veratic acid and SUL (internal standard) after 12 h of oral
after fitting the data into Peppas equation. The value of “n” administration of FRS FRS-11 is shown in Figure 9.
was calculated to characterize the release as either Fickian Results revealed that after oral administration of FT-10,
diffusion n 0 or anomalous diffusion (non-Fickian), 0.5 FRS-11, and market product to beagle dogs, the drug
n 1.52 The n values for FT-11and F-12 were 0.59 and appeared in plasma after 0.53 0.12 h, 0.51 0.1 h, and
0.61, respectively, which indicates a non-Fickian diffusion 0.70 0.24 h, respectively. Mean peak drug concentration

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 R2 First-order R2 Higuchi Korsmeyer– Hixson
model R2 Peppas model Crowell
R2 n model R2

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.

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Dovepress Bioavailability study of floating systems

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.
of FRS-11 Cmax (2.37 0.15 g/mL) was higher than that of Abbreviations: HPLC, high-performance liquid chromatography; SUL, Sulpiride;
FRS, floating raft system; TIC, time incident concentration.
the market product “Duspatalin® SR” (2.309 0.51 g/mL)
and FT-10 (2.306 0.42 g/mL). The mean time to reach the
peak concentration (tmax) was comparable, and no statisti- polymer and the formation of dense internal structure matrix,
cally significant difference (P 0.05) was observed among which increases the ability of the raft system to entrap drug
the tmax values of the three samples. Moreover, there was no and decrease the loss of drug in the curing medium, and
significant difference (P 0.05) in the terminal elimination 2) the higher polymer concentration in the raft system, which
rate constant among the three products. The AUC0–24 value increases the viscosity and swelling of the polymer matrix as
was 68.89 6.36, 72.17 8.17, and 79.92 10.12 ( g h mL 1) well as the formation of a swollen gel with longer diffusion
for the market product, FT-10, and FRS-11, respectively, path length that could substantially reduce the penetration
suggesting that FRS (FRS-11) showed the highest rate of the dissolution medium, so the drug release was retarded.
and extent of drug absorption, whereas the market product ANOVA applied to log AUC0– and log Cmax data as recom-
showed the lowest rate and extent of drug absorption. The mended by USP 24 are shown in Table 5. There are no sta-
relative bioavailability of FT-10 and FRS-11 were 104.76% tistical significant differences between the values of AUC0–
and 116.01%, respectively. and Cmax calculated for both formulations.
The higher bioavailability of the raft system may be
interpreted on the basis of, 1) higher viscosity of Precirol Conclusion
This study has demonstrated the suitability of using hydro-
Table 4 Mean pharmacokinetic parameters of MbH obtained philic polymers with lipid polymer to sustain drug release
after oral administration of Duspatalin® SR, floating matrix tablet from FTs and raft systems. According to the above results,
(FT-10), and in situ raft system (FRS-11) to beagle dogs
optimum formulations from both FTs and FRSs were able
Parameters Formulations
to control drug release along with acceptable FLt and total
Duspatalin® FT-10 FRS-11
floating time 12 h. The in vitro drug release profile was
AUC0–24 h ( g h mL 1) 68.89 6.36 72.17 8.17 79.92 10.12
modified by using different lipid polymers in different ratios.
AUC0– ( g h mL 1) 69.51 6.32 77.69 8.90 91.98 11.13
Cmax ( g mL 1) 2.309 0.51 2.306 0.42 2.373 0.15
Analysis of the release profiles indicated that drug release
tmax (h) 3.33 1.0 2.17 1.2 3.0 1.6 from optimum formulations occurred through diffusion
Kel 0.149 0.033 0.138 0.034 0.126 0.033 according to Fickian diffusion release mechanism. Both
t1/2 4.84 1.1 5.45 1.8 5.85 1.7
floating matrix and raft system showed higher relative bio-
F 104.76 116.01
availability of MbH than the reference “Duspatalin®200 SR.”
Note: Data presented as mean standard deviation (n 6).
Abbreviations: ANOVA, analysis of variance; AUC, area under the curve; Cmax, These results demonstrated that both controlled-released FT
peak plasma concentration; FT, floating matrix tablet; FRS, floating raft system; Kel,
elimination rate constant; MbH, Mebeverine HCl; SR, sustained release; tmax, time to
and raft system using hydrophilic and lipid polymer would
reach maximum peak. be promising gastroretentive delivery systems for prolonging

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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: commercial FT10 FRS11
The medians of tmax
The alternative hypothesis here is that at least two treatments’ means differ are the same across
different treatments
P-value (The significance level is 0.05)
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; Kel, elimination rate constant; MbH,
Mebeverine HCl; tmax, time to reach maximum peak.

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The authors report no conflicts of interest in this work.
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