Doodipala et al: Development and Clinical PK Evaluation of Gastroretentive Floating Matrix Tablets of Levofloxacin

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International Journal of Pharmaceutical Sciences and Nanotechnology

Volume 4 Issue 3 October December 2011
MS ID: IJPSN-07-12-11-NARENDER

Research Paper

Pharmaceutical Development and Clinical Pharmacokinetic

Evaluation of Gastroretentive Floating Matrix Tablets of
Levofloxacin
N. Doodipala, C.R. Palem, S. Reddy and Y. M. Rao*
National Facilities in Engineering and Technology with Industrial Collaboration Centre, University College of Pharmaceutical
Sciences, Kakatiya University, Warangal506 009, Andhra Pradesh, India.
Received July 12, 2011; accepted October 31, 2011

ABSTRACT
The most common approach for achieving sustained drug
release is by the use of hydrophilic polymeric excipients
directly compressed with active ingredients into tablets.
Hydrophilic polymers swell in the presence of water to form
hydrogel structures from which drugs are released by slow
diffusion. The purpose of this study was to prepare a floating
drug delivery system of levofloxacin, a fluoroquinolone
antibiotic. Levofloxacin is highly soluble in acidic media and
precipitates in alkaline media, thereby losing its solubility. We
designed a gastroretentive system of levofloxacin to enhance
bioavailability by retaining them in the acidic environment of
the stomach. Tablets were prepared by the direct compression
technique using polymers such as hydroxypropylmethylcellulose (HPMC K4M, HPMC K15M, and HPMC
K100M). Sodium bicarbonate was utilized as a gas-generating

agent. Tables were evaluated for their physical characteristics

such as hardness, thickness, friability, weight variation, drug
content, swelling studies, and floating properties. Tablet
formulations were evaluated by in vitro dissolution studies.
Formulations showed a floating lag time of 30 seconds and a
floating time above 12 hours. Among these formulations F3, F7
and F11 exhibited controlled and prolonged drug release
profiles while floating over the dissolution medium. The best
formulation (F3) was selected based on in vitro characteristics
and further tested in healthy volunteers by radiographic
studies of tablets by incorporating BaSO4. These clinical
studies revealed that the tablets remained in the stomach for
240 30 minutes in fasting human volunteers, indicating
gastric retention of the system.

KEYWORDS: Levofloxacin; floating matrix tablets; gastric retention; radiographic studies.

Introduction
Helicobacter pylorus (H. pylori) has been recognized
as a major gastric pathogen with worldwide distribution.
H. pylori is a causative organism in chronic active
gastritis, duodenal ulcers, and gastric adenocarcinoma
(Forman et al., 1994; Negrayd and Kaniykuattem 1992).
The pathogen is susceptible to many antibiotics in vitro,
but it is difficult to eradicate from the human body.
Extended resident time of the antimicrobial agents is
desirable for effective eradication of H. pylori. In order to
extend the gastric residence period, a number of
approaches have been developed such as floating drug
delivery systems, swelling and expanding systems,
polymeric bioadhesive systems, modified shape systems,
high-density systems and other delayed gastric emptying
devices (Brazel and Peppas, 2000; Bardonn et al., 2006;
Bomma et al., 2009; Bandari et al., 2010).
The gastroretentive floating drug delivery system
(GRFDDS) has a bulk density lower than gastric fluids
and thus remains buoyant in the stomach without
affecting the gastric emptying rate for a prolonged period

of time (Park and Park, 1998; Singh and Kim, 2000;

Klaussner et al., 2003; Patel and Patel, 2006). While the
system is floating on the gastric content, the drug is
released slowly at a desired rate from the system.
Floating drug delivery systems offer important
advantages: they are less prone to gastric emptying
resulting in reduced intra- and inter-subject variability
in plasma drug levels, effective for delivery of drugs with
narrow absorption windows, require reduced dosing and
increased patient compliance, reduced Cmax and
prolonged drug levels above the minimum effective
concentration, and they provide an improved safety profile
for drugs with side-effects associated with high Cmax.
The
various
buoyant
preparations
include
microballoons, granules, powders, capsules, tablets, and
laminated films. Based on the mechanism of buoyancy,
two distinctly different technologies, non-effervescent
and effervescent systems, have been utilized in the
development of floating systems (David et al., 1986;
Chavanpatil et al., 2005; Hamid et al., 2006; Janardhan
et al., 2009; Meka et al., 2009). Non-effervescent systems
commonly use gel-forming or highly swellable cellulose
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Int J Pharm Sci Nanotech

type hydrocolloids, polysaccharides and matrix forming

polymers
such
as
polycarbonate,
polyacrylate,
polymethacrylate, and polystyrene (Rosa et al., 1994;
Lapidus and Lordi, 1966). Effervescent systems utilize
matrices prepared with swellable polymers such as
methocel or chitosan and effervescent compounds such as
sodium bicarbonate and citric or tartaric acid or matrices
containing chambers of liquid that gasify at body
temperature (Korsmeyer et al., 1983; Hoffman et al.,
1986; Park and Park, 1998; Singh and Kim, 2000).
Levofloxacin is a widely used synthetic fluorinated
quinolone antibiotic. Chemically, levofloxacin is (-)-(S)-9fluro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperzinyl)-7oxo-7H-pyrido-[1,2,3-de]-1,4-benzoxazine-6-caboxylic acid.
Levofloxacin acts by inhibiting bacterial DNA gyrase
enzyme that is required for DNA replication and thus
causes bacterial lyses. It is effective for the treatment of
H. pylori (Warren and Marshal, 1983; Okeri and
Arhewoh, 2008). The failure of the antibiotic therapy can
be avoided by providing the effective concentration of the
drug at the site of action. Levofloxacin has a half-life of
5-7 hours and 85% oral bioavailability.
In this study, we sought to develop a site-specific
sustained dosage form of levofloxacin using three
grades of hydrophilic matrix agents. The formulation
was characterized by in vitro and in vivo release studies
including clinical kinetic testing of drug product in healthy
human volunteers to assess the gastric residence time.

Materials and Methods

Drugs and Chemicals
Levofloxacin was generous gift from Euro Drugs
(Hyderabad, India). HPMC K4M, HPMC K15M and
HPMC K100M were obtained from ISP, India. Sodium
bicarbonate, citric acid, talc and magnesium stearate
were purchased from S.D. Fine Chemicals Ltd (Mumbai,
India). All chemicals and drugs were of analytical grade.

Formulation and Evaluation Methodology

Vol 4;Issue 3OctoberDecember 2011

drug- to-polymer ratio and effervescent composition. The

formulations were prepared with varying proportions of
4:1, 3:1 and 1:1 (12.5% from the total weight of the
tablet) of a gas-generating agent composition (sodium
bicarbonate: citric acid) in order to determine the effect of
gas-generating agent concentration on the buoyancy
behavior of the formulations.
Drug-excipients compatibility study.

Differential scanning calorimetry (DSC): The DSC

thermograms were recorded on a DSC (model Dsc-60,
Shimadzu). Samples were heated in hermetically sealed
aluminum pans over a temperature range of 10oC-300oC
at a constant rate of 10oC/minutes under nitrogen purge.
Fourier Transform Infra Red Spectroscopy (FTIR):

FTIR spectra were obtained on FTIR-8400S (Shimadzu).

Samples were prepared in KBr disks. Data were collected
over a spectral region from 4000 to 400 cm-1.

Preparation of LFH floating tablets. Preliminary

formulations were studied to optimize the effervescent
composition. Then, the floating tablets were prepared
with an optimized concentration of gas-generating agent.
The powder mixture containing drug, polymers and other
excipients were weighed as per required quantity and
thoroughly blended in mortar and pestle and then passed
through sieve no. 40 and directly compressed using 8 mm
flat punches on a rotary compression machine (Riddhi,
India). The compression force was adjusted to obtain
tablets with crushing strength in the range of 6 to 7
kg/cm2. Twelve batches of tablets were prepared by direct
compression technique according to the formula depicted
in Table 1.
Evaluation of final blend. The flow properties of granules
(before compression) were characterized in terms of angle
of repose, tapped density, bulk density and the Carrs
index and Hausner ratio.
Evaluation
of
physicochemical
properties.
The
formulated tablets were evaluated for weight variation,
thickness, crushing strength, friability, content
uniformity, in vitro buoyancy properties, in vitro release
studies and in vivo residence time.

Optimization of gas-generating agent concentration.

Preliminary formulations were studied to optimize the
TABLE 1
Composition of levofloxacin floating tablets.
Formulation

HPMCK4M

HPMCK15M

HPMCK100M

Sodium bicarbonate

Citric acid

MCC

F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12

--------50
75
100
125

50
62.5
75
87.5
---------

----25
50
62.5
75
-----

50
50
50
50
50
50
50
50
50
50
50
50

12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5

127.5
115
102.5
90
152.5
127.5
115
102.5
127.5
85.5
60.5
45.5

All the tablets contain 250 mg levofloxacin, 5 mg magnesium stearate and 5 mg talc.
The average weight of each formulation was 500mg.

Doodipala et al: Development and Clinical PK Evaluation of Gastroretentive Floating Matrix Tablets of Levofloxacin

Weight variation: 20 tablets were selected at random

and the average weight of the tablets was determined.
The weight of individual tablets was compared with the
average weight.
Thickness: The thickness in millimeters (mm) was
measured individually for 10 pre weighed tablets by
using Vernier Calipers. The average thickness and
standard deviation were reported.
Crushing strength and friability: Crushing strength
of tablet was determined by the Monsanto tester
(Campbell Electronics, India) hardness tester. Friability
tests were carried out using a Roche friabilator (Erection
Instrument & Engineering, Ahmedabad, India). 10
tablets were weighed and subjected to the combined
effect of attrition and shock by utilizing a plastic
chamber. The friabilator was operated for 100
revolutions (4 minutes, 25 rpm). The tablets were
dedusted and re-weighed to calculate the percentage of
friability.
Drug content uniformity: Prepared tablets were
accurately weighed and finely powdered by pestle in a
mortar. A weighed portion of each powder equivalent to
dose (mg) of the prepared tablet was transferred in to a
volumetric flask and the drug was extracted with
methanol as the solvent. The contents of the flask were
sonicated for 10 min and diluted with 0.1 N HCl as the
solvent. The samples were analyzed spectrophotometrically at 293 nm.
In vitro buoyancy studies: The in vitro buoyancy was
determined by the method described by Rosa et al. The
tablets were placed in a 100 ml beaker containing 0.1 N
HCl. The time required for the tablet to rise to the
surface was determined as floating lag time and duration
of the tablet remaining buoyant was observed visually.
In vitro release studies: The release of LFH from
floating matrix tablets was studied using the USP (11)
dissolution apparatus II (Tab Machines, India). The
dissolution medium was 900 ml of 0.1 N HCl maintained
at 37C 0.5C with a rotation speed of 50 rpm. Aliquots
of 5 ml were collected at predetermined time intervals,
filtered through a 0.45 mm membrane filter and
replenished with an equivalent volume of fresh medium.
Drug contents in the samples were determined by a UVvisible double beam spectrophotometer (Elico, India) at
293 nm.

Intra-gastric Behavior of the Floating Tablets in

Human Subjects
The intra-gastric behavior of the floating tablets was
carried out by administering the LFH floating matrix
tablets to healthy human male volunteers and
monitoring them through a radiological method. To make
the tablets X-ray opaque, the incorporation of BaSO4 was
necessary. The amount of the X-ray opaque material in
these tablets was sufficient to ensure visibility by X-ray,
but at the same time this amount of BaSO4 was low
enough to enable tablets to float. Four healthy male
subjects (mean age, 27 years; mean body weight, 60 kg)
participate after giving informed consent. The study was

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approved by the Ethical Committee (UCPSc, Kakatiya

University, Warangal). The study was conducted by
administering to each subject one floating tablet on
during a fasted state; the subjects fasted overnight then
swallowed the floating tablets with 150 ml of water.
Afterwards, the subjects were not allowed to eat or drink.
In each subject, the position of the floating tablet was
monitored by X-ray photographs (Konica Minolta,
Siemens, Karlsruhe, Germany) of the gastric region at
determined time intervals. All X-ray films were taken in
anterior positions.

Results and Discussion

IR Spectroscopic Studies
IR spectroscopic studies were conducted to determine
possible drug-polymer interactions. IR spectra of pure
drug levofloxacin hemihydrate, HPMC K4M, K15M,
K100M and physical mixtures of levofloxacin
hemihydrate with these polymers were obtained which
show all the characteristic peaks of levofloxacin
hemihydrate and polymers present in the physical
mixture. The major peaks C=O peak at 1724.81 cm-1,
aromatic C-H peak at 2935.62 cm-1 (Figure 1) and OH
group of carbonyl moiety at 3265.81 cm-1 which were
present in pure drug levofloxacin hemihydrate was also
present in the physical mixture, which indicates that
there is no interaction between drug and the polymers,
which confirms the stability of drug.
The pure drug showed a sharp endothermic peak at
227 oC corresponding to its melting point. The polymers
showed endothermic peaks of 252.5 oC and 255 oC
(Figure 2) respectively. The appearance of two or more
endothermic peaks in the heating DSC curves of
levofloxacin hemihydrate-polymers may be an indication
of the stability of drug.
The tablets of LFH were prepared by direct
compression using HPMC K4M, HPMC K15M and
HPMC K100M, sodium bicarbonate and citric acid.
Magnesium stearate and talc were used as lubricant and
glidant, respectively. The data of physical parameters
like thickness, weight variation, content uniformity,
friability of all the formulations is enclosed in Table 2.
All parameters fall within the limits. The average weight
of the tablets was 500 mg and the weight variation for
every batch was less than 5%. The hardness was
maintained as 6.5-7 kg/cm2 in all the formulations. The
friability of all the formulations falls in the acceptable
limit. The content uniformity was found to be in range of
96.3398.56%.

In vitro Buoyancy Studies

The prepared floating matrix tablets were buoyant for
12 hours with a floating lag time of less than 70 seconds.
The optimized concentration of the effervescent mixture
(sodium bicarbonate and citric acid) contributed to the
buoyancy of all tablets. Buoyancy results of floating
matrix tablets are shown in Table 3.

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Fig. 1. FTIR spectra of A)

LFH, B) LFH & HPMCK4 C)
LFH and HPMC K15M D)
LFH and HPMC K100M E)
Optimized formulation (F3).

Fig. 2. DSC thermograms of

A) LFH, B) LFH & HPMC
K15 C) LFH and K4M and D)
Optimized formulation (F3).

TABLE 2
Physical evaluation parameters.
Formulation code

Weight
variation (mg)a

Hardness
(kg/cm2)b

Thickness
(mm)

Friability (%)

F1

503 1.2

6.80.5

6.760.06

0.23

98.56 1.2

F2

502 1.1

70.3

6.860.03

0.48

98.21 1.6

F3

503 1.2

6.50.5

6.760.04

0.51

97.91 1.5

F4

501 1.3

6.80.2

6.630.06

0.22

97.75 1.6

F5

502 1.2

6.80.5

6.680.05

0.35

97.48 1.4

F6

501 1.1

70.2

6.550.25

0.38

97.69 1.3

F7

503 1.2

6.80.5

6.50.04

0.41

97.35 1.6

F8

505 1.4

6.50.3

6.620.07

0.29

96.55 1.4

F9

501 1.3

70.3

6.560.07

0.25

97.41 1.2

F10

500 1.4

7.20.1

6.480.04

0.28

97.97 1.2

F11

505 1.4

6.80.2

6.610.06

0.39

96.54 1.3

F12

504 1.7

7.20.5

6.940.08

0.48

96.33 1.4

Mean SD: a n = 20, b n = 6, c n = 3.

Drug Content (%)c

Doodipala et al: Development and Clinical PK Evaluation of Gastroretentive Floating Matrix Tablets of Levofloxacin
TABLE 3
Floating properties of prepared tablets.
Formulation
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12

Floating lag time (sec)

55
58
61
60
68
66
65
66
58
55
51
48

Floating time (h)

>12
>12
>12
>12
>12
>12
>12
>12
>12
>12
>12
>12

In vitro Release Studies

The in vitro drug release studies revealed that
formulations F1 and F2 showed a release of 91.9% and
97.04%, respectively, in 8 and 10 hours (Figure 3A).
Formulation F3 showed the maximum drug release of
98.7% in 12 hours. The variation in drug release was due
to different polymer concentrations in all four
formulations. Formulations F1 and F2 were unable to
sustain the drug release desired period of time but in the
case of formulation F3, 98.7% and 73.31% of drug was
released in 12 hours. This could be due to different
polymer concentrations in all the four formulations. All
four formulations floated for 12 hours. Formulations F4
failed to release the required drug profile. Formulation
F3 obtained the desired drug release profile and floated
with a lag time of 65 seconds and for these reasons, it
was considered as best formulation among the four.
Formulations F5-F8, composed of HPMC K100M,
showed a release of 93.4, 95.7, 96.8 and 80.9% in 4, 8,
and 12 hours, respectively. These variations in drug
release were due to changes in polymer concentrations of
the tablets. However, formulations F5, F6 and F9 failed
to meet the desired drug release profile in 12 hours.
Formulation F8 met the desired drug release profile in

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12 hours and floated with a lag time of 55 seconds. It

was, therefore, considered the best formulation among all
the four formulations in this series. The results are
shown in Figure 3B.
The drug release from the floating matrix tablets was
sustained for a prolonged period of time due to the
viscous nature of the HPMC matrix through which the
drug diffuses. HPMC K4M helped to increase the drug
release within 12 hours and maintained the integrity and
buoyancy of the tablets but floating lag time decreased
with increased concentration. The results are shown in
Figure 3C. The increased drug release from the floating
matrix tablets with high concentration of HPMC K4M
compared to the floating matrix tablets containing a
smaller amount may be due to matrix erosion in the
former and swelling diffusion and a slight erosion
mechanism in the latter. However, the matrix containing
a high viscosity grade of polymer with a large molecular
mass mainly results in swelling properties with little
erosion and vice versa. Integrity and floating properties
of floating matrix tablets were thus maintained. The
drug released was found to be 97.2% 12 hours from
formulation F11.
Data of the in vitro release was fit into kinetic models
to explain the release kinetics of LFH from the floating
tablets (Higuchi, 1963; Hoffman et al., 1986; Gohel et al.,
2000). The kinetic models used were zero-order equation,
first-order equation, and Higuchi and KorsemeyerPeppas models. The cumulative amount of the drug
released from the tablets, when plotted against squareroot of time, the release profiles of the drug seem to
follow the Higuchi model, as it was evidenced by
correlation coefficients (r2 = 0.98 to 0.99) better than zero
order (r2 = 0.93 to 0.98) and first order (r2 = 0.52 to 0.57).
The data was further treated as per the following
equation:
Mt/M = K.t.n

Fig. 3A. Drug release profiles of

LFH floating matrix tablets
composed of HPMC K15M (F1,
F2, F3 and F4).

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Vol 4;Issue 3OctoberDecember 2011

Fig. 3B. Drug release profiles of LFH

floating matrix tablets composed of
HPMC K100M (F5, F6, F7 and F8).

Fig. 3C. Drug release profiles of LFH

floating matrix tablets composed of
HPMC K4M (F9, F10, F11 and F12).

Where, Mt/M is the fractional release of the drug,

Mt is the amount released at time t, M is the total
amount of drug contained in the formulation, t is the release
time, K is a kinetic constant, and n is the diffusional
release exponent indicative of the operating release
mechanism.
The n values obtained (0.487 to 0.5) by this equation
indicated that the drug release was by a non-Fickian
model. The results are shown in Table 4.

In Vivo Radiographic Studies in Human Subjects

The optimized formulation was selected based on the
correlation factor (r2) values of all formulations and
dissolution parameters and physical characteristics of
formulation. Formulation (F3) selected as optimized
and in vivo X-ray studies revealed that tablets float in the

stomach for 240 30 minutes in healthy human volunteers

in fasting conditions and the results are shown in Figure 4.
TABLE 4
Correlation coefficient (R2) and release exponent (n) values for
different kinetic models.
Formulation

zero-order

First-order

Higuchi

F1
F2
F3
F4
F5
F6
F7
F8
F9

0.896
0.944
0.972
0.961
0.982
0.89
0.928
0.934
0.954

0.491
0.451
0.469
0.533
0.497
0.449
0.454
0.483
0.455

0.991
0.979
0.995
0.991
0.913
0.992
0.995
0.997
0.994

Korsmeyer
Peppas
0.487
0.69
0.251
0.534
0.49
0.371
0.435
0.504
0.464

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Fig. 4. Radiographic images showing the presence of a BaSO4-loaded floating tablet in the stomach at different time periods (the tablet is
indicated with an arrow). The tablet altered its position in the stomach. Images were taken after: a) 0.5 h , b) 1.5 h, c) 3 h and d) 4 h after
tablet administration (n=4 subjects).

Conclusions
Overall, the results of the present study suggest that
effervescent-based floating drug delivery is a promising
approach to achieve excellent in vitro buoyancy. The
addition of gel-forming polymer (HPMC K4M, HPMC
K15M and HPMC K100M) and a gas-generating agent
such as sodium bicarbonate is essential to achieve
optimum in vitro buoyancy. Our results suggest that
formulation F3 showed controlled drug release and has
adequate floating properties. The kinetics of drug release
can be best explained by the Higuchi model. Our clinical
pharmacokinetic studies indicate that the tablets floated
in the stomach for over 4 hours in healthy volunteers,
indicating that gastric retention time can be successfully
achieved by the floating principle.
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Address correspondence to: Prof. Y. Madhusudan Rao, National Facilities
in Engineering and Technology with Industrial Collaboration Centre,
University College of Pharmaceutical Sciences, Kakatiya University,
Warangal-506 009, AP, India. E-mail: [email protected]