Journal of Controlled Release 168 (2013) 151165

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Journal of Controlled Release

journal homepage: www.elsevier.com/locate/jconrel

Review

Raft forming systemAn upcoming approach of gastroretentive drug

delivery system
Vipul D. Prajapati , Girish K. Jani, Tohra A. Khutliwala, Bhumi S. Zala
Department of Pharmaceutics, S.S.R. College of Pharmacy, Sayli-Silvassa Road, U.T. of Dadra and Nagar Haveli-396230, India

a r t i c l e i n f o a b s t r a c t

Article history: In recent era various technologies have been made in research and development of controlled release oral
Received 17 October 2012 drug delivery system to overcome various physiological difculties such as variation in gastric retention
Accepted 26 February 2013 and emptying time. To overcome this drawback and to maximize the oral absorption of various drugs,
Available online 14 March 2013
novel drug delivery systems have been developed. Gastroretentive drug delivery system is facing many chal-
lenges which can be overcome by upcoming newly emerging approach i.e. raft forming system. The purpose
Keywords:
Gastroretentive form
of writing this review is to focus on recent development of stomach specic oating drug delivery system to
Raft forming system circumvent the difculties associated with formulation design. Various gastroretentive approaches that have
Gastric residence time been developed till now are also discussed. The present study provides valuable information & highlights ad-
Gastric emptying time vances in this raft forming system. This review attempts to discuss various factors like physiological factors,
Migrating myoelectric cycle physicochemical factors and formulation factors to be considered in the development of the raft forming sys-
tem. Different types of smart polymers used for their formulation have also been summarized. The review fo-
cuses on the mechanism, formulation and development of the raft forming system. This review also
summarizes the studies to evaluate the performance and application of these systems. The study nally high-
lights advantages, disadvantages, and marketed preparation of the raft forming system.
2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
2. Anatomical and physiological aspects of the stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2.1. Anatomy of the stomach GIT [2629] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2.2. Physiology of the stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
3. Factors controlling the gastroretentive drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.1. Factors related to the dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.1.1. Size of the dosage form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.1.2. Shape of dosage form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.1.3. Density of dosage form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.2. Food intake and its nature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.2.1. Fed & unfed stateunder fasting condition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.2.2. Food intake & nature of food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.2.3. Calorie content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.2.4. Frequency of feed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.3. Patient related factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.3.1. Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.3.2. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.3.3. Posture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.3.4. Concomitant drug administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.4. Disease state . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3.5. Volume of the GI uid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3.6. Effect of gastrointestinal uid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Corresponding author at: Department of Pharmaceutics and Pharmaceutical Technology, SSR College of Pharmacy, Sayli-Silvassa Road, Sayli, Silvassa, U.T. of Dadra and Nagar
Haveli-396230, India. Tel.: +91 9824284159; fax: +91 260 2681104.
E-mail address: vippra2000@yahoo.com (V.D. Prajapati).

0168-3659/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jconrel.2013.02.028
152 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165

4. Different gastroretentive forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

4.1. High-density systems/non-oating system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
4.2. Low density system/oating system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
4.2.1. Non effervescent system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
4.2.2. Effervescent system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
4.3. Bioadhesive systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
4.4. Swelling systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
4.5. Expandable systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
4.6. Superporous hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4.7. Magnetic systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4.8. Ion exchange resin system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
5. Raft forming system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
5.1. General consideration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
5.2. The design of the raft forming system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
5.3. Ingredient used in the formulation of the raft forming system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
5.3.1. Drugs used for the raft forming system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
5.3.2. Polymer used for formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
5.4. Approaches used for the formulation of the raft forming drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.4.1. Raft formation based on physical mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.4.2. Raft formation based on chemical mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
5.4.3. Raft formation based on physiological stimuli mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
5.5. Advantages of oating raft forming gastroretentive drug delivery system over other gastroretentive drug delivery system . . . . . . . 161
5.6. Limitation of oating raft forming gastroretentive drug delivery system over other gastroretentive drug delivery system . . . . . . . . 161
5.7. Evaluation parameters of the raft forming system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
5.7.1. In vitro evaluation parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
5.7.2. In-vivo evaluation test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
6. Marketed formulation of the raft forming system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
7. Patented preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
8. Advances in raft forming approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

1. Introduction drug in a controlled manner, so that the drug could be supplied contin-
uously to its absorption sites in the gastrointestinal tract [4]. Therefore,
The purpose for designing any drug delivery system is to deliver a system is necessary to be designed that permits longer gastric resi-
the drug directly to the site of action to achieve and maintain the de- dence which will extend the time within which drug absorption can
sired drug concentration in the body. Over the past few years atten- occur in the small intestine.
tion has been focussed on development of controlled and sustained To formulate a site-specic orally administered conventional con-
drug delivery systems. Extensive research has been carried out in de- trolled release dosage form, it is desirable to achieve prolong gastric
signing of sustained drug delivery systems. Various drug delivery sys- residence time by the drug delivery system. GRDDS is the system in
tems are used for maximum therapeutic efcacy and reduction in the which a drug can remain in the gastric region for several hours in
side effects of the drug. Among the various routes oral route became order to prolong its gastric residence time. Rapid gastrointestinal
the most preferred, promising and effective route for the administra- transit of conventional GRDDS can prevent complete drug release at
tion of therapeutic agents, because of its numerous advantages like gastric region and reduce the efcacy of the administered dose of
low cost of therapy, ease of administration, exibility in formulation, drugs as the majority of drugs are absorbed in the stomach or the
delivery of drugs for longer period of time and its better bioavailabil- upper part of the small intestine [6,7]. To overcome this limitation, a
ity which leads to higher level of patient compliance. Approximately modied GRDDS is preferred (Fig. 1).
50% of the drug delivery systems available in the market are oral
drug delivery system [1].
It is clear from the recent research and patent literature that there
is an increased interest in novel dosage forms that are retained in
the stomach for a prolonged and predictable period of time [2].
Gastroretentive drug delivery system (GRDDS) is one of the novel ap-
proaches in this area. Oral controlled release dosage forms are the
most commonly acceptable formulations but still offer highest atten-
tion in the area of novel drug delivery systems [3].
Drugs that are easily absorbed from the gastrointestinal tract (GIT)
and have short half-lives are eliminated quickly from the systemic cir-
culation. Frequent dosing of these drugs is required to achieve suitable
therapeutic activity. To avoid this limitation, the developments of oral
sustained-controlled release formulations are an attempt to release
the drug slowly into the GIT and maintain an effective drug concentra-
tion in the systemic circulation for a long time. After oral administration, Fig. 1. Drug absorption in: (A) conventional dosage form and (B) the gastroretentive
such a drug delivery would be retained in the stomach and release the drug delivery system.
 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165 153

Thus GRDDS are benecial with reference to their bioavailability,

therapeutic efcacy and possible reduction of the dose and improve
the drug solubility that is less soluble in a high pH environment [8].
Apart from these advantages, these systems offer various pharmaco-
kinetic advantages like maintenance of constant therapeutic levels
over a prolonged period and thus reduction in uctuation in the ther-
apeutic levels [9]. Gastric residence will provide advantages such as
the delivery of drugs with narrow absorption windows in the small
intestinal region. Also prolonged gastric retention time in the stom-
ach could be advantageous for local action in the upper part of the
small intestine.
Various approaches have been proposed to increase gastric residence
of drug delivery systems in the upper part of the gastrointestinal tract
that includes oating drug dosage systems (FDDS). The approaches are
low density systems [10], high density systems [11,12], mucoadhesion
or bioadhesion systems [13], expansion systems [14,15], magnetic sys-
tems [1618], Superporous hydrogel [19,20], raft forming systems
[2123] and oating ion exchange resins [24].
Among these systems, the raft forming system has been most com-
monly used as it is one of the most feasible & preferred approaches for
achieving a prolonged and predictable drug delivery prole in the GI
tract. This system is capable of releasing a drug molecule in a sustained
manner affording relatively constant plasma proles. These hydrogels Fig. 2. Anatomy of the gastrointestinal tract.
are liquid at room temperature but undergo gelation when in contact
with body uids or change in pH. The goal for designing this system is
to reduce the frequency of dosing or to increase effectiveness of the The proximal part is made of fundus, body acts as a reservoir for
drug by localization at the site of the action, decreasing the dose re- undigested material & antrum acts as a pump for gastric emptying
quired or providing uniform drug delivery. The raft forming system by propelling actions. Antrum is a major site of mixing. Due to its
also possesses some potential advantages like simple manufacturing small surface area very little absorption takes place from the stomach.
processes, better patient compliance and ease of administration [5,25]. It provides barrier to the delivery of drugs to the small intestine [26]
(Fig. 3).
2. Anatomical and physiological aspects of the stomach
2.2. Physiology of the stomach
2.1. Anatomy of the stomach GIT [2629]
The GIT is always in a state of continuous motility. There are
The gastrointestinal tract can be divided into three main regions. two modes of motility pattern such as (a) the digestive mode and
They are namely (b) interdigestive mode.
Gastric emptying occurs during fasting as well as fed states. In case
1. Stomach of fasted state an interdigestive series of electrical events occurs in cy-
2. Small intestineduodenum, jejunum and ileum clic manner both through the stomach and the small intestine every
3. Large intestine 23 h. This electrical activity is termed as interdigestive myoelectric
cycle or migrating myoelectric complex (MMC) [30,31].
The GIT (gastrointestinal tract) is a continuous muscular tube, The migrating myoelectric complex (MMC) is further divided into
extending from the mouth to the anus. The GIT is like a tube of 9 m four phases (Fig. 4):
long that starts from the mouth & ends with the anus (Fig. 2). The
function is to take in nutrients and eliminate waste by such physio- PHASE I: It is quiescent period with rare contraction & lasting from
logical processes such as secretion, motility, digestion, absorption 30 to 60 min.
and excretion. The walls of the GIT, from the stomach to the large in- PHASE II: It consists of intermittent action potentials & contraction
testine, have different layers of tissue from outside to inside. The that gradually increases intensity & frequency as the phase pro-
stomach has a third muscle layer known as the oblique muscle gresses. It lasts for 2040 min.
layer which is situated in the proximal stomach, branching over
the fundus and higher regions of the gastric body. The different
smooth muscle layers are responsible for performing the motor func-
tions of the GIT, i.e. gastric emptying and intestinal transit.
The stomach is a J-shaped organ. It is located in the upper left
hand portion of the abdomen, just below the diaphragm. It occupies
a portion of the epigastria and left hypochondriac region. The main
function of the stomach is to store the food temporarily, grind it and
then release it slowly into the duodenum [30]. Since the drugs are
absorbed in the upper small intestine, it will be benecial to develop
the dosage forms that reside in that region [27,28].
The stomach is divided into 3 anatomical regions:

1. Fundus
2. Body
3. Pylorus (antrum) Fig. 3. Physiology of the stomach.
154 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
Fig. 4. Schematic representation of the interdigestive motility pattern, frequency of
contraction forces during each phase and average time period for each period.
PHASE III: It is for short period of intense, large regular contraction
from 10 to 20 min, and it sweeps the undigested material from the
stomach to the small intestine. Phase III is termed as housekeeper
wave as it enables to sweep away all undigested materials out of
the stomach & down to the small intestine. Between phase III &
phase I of two consecutive cycles a brief transitional phase IV occurs.
PHASE IV: Short transitional phase of about 0 to 5 min.
In fed state gastric emptying is slow. The motor activity in the fed
state is induced 510 min after ingestion of a meal and persists as
long as food remains in the stomach. The larger the amount of food
ingested, the longer the period of fed activity, with usual time spans
of 26 h. When GRDDS are administered in the fasted state, the
MMC may be in any of its phases, which can signicantly inuence
the total gastric retention time (GRT) and transit time in the gastroin-
testinal tract.
3. Factors controlling the gastroretentive drug delivery system
There are various factors to be considered for the development of
gastroretentive dosage forms formulation to prolong the dosing inter-
vals and thus improve patient compliance. They are shown below.
3.1. Factors related to the dosage forms
3.1.1. Size of the dosage form
To allow the dosage form to pass through the pyloric valve into the
small intestine the particle size should be in the range of 1 to 2 mm.
In most cases, the larger the dosage form the greater will be the GRT.
Due to the larger size of the dosage form, it could not quickly pass
through the pyloric antrum into the intestine [19]. Small-size tablets
leave the stomach during the digestive phase while the large-sized tab-
lets are emptied during the housekeeping waves.
3.1.2. Shape of dosage form
Ring-shaped and tetrahedron-shaped devices have a better gastric
residence time as compared to other shapes [32].
3.1.3. Density of dosage form
Dosage forms having a density lower than the gastric contents can
oat to the surface, while high density systems sink to the bottom of
the stomach. Both positions may isolate the dosage system from the py-
lorus. A density of b1.0 g/cm3 is required to exhibit oating property
[33]. However the oating tendency of the dosage form usually de-
creases as a function of time, as the dosage form gets immersed into
the uid, as a result of the development of hydrodynamic equilibrium
[34].
3.2. Food intake and its nature
3.2.1. Fed & unfed stateunder fasting condition
Under fasting conditions, the gastrointestinal motility is character-
ized by periods of strong motor activity or MMC that occurs every 1.5
to 2 h. The MMC sweeps the undigested material from the stomach
and if the timing of administration of the formulation coincides
with that of the MMC, the GRT of the unit can be expected to be
very short. However, in the fed state, MMC is delayed and GRT is con-
siderably longer [35].
3.2.2. Food intake & nature of food
Food intake, viscosity and volume of food, caloric value and fre-
quency of feeding have a profound effect on the gastric retention of
dosage forms. The presence or absence of food in the gastrointestinal
tract inuences the gastric retention time of the dosage form. Usually
the presence of food in the gastrointestinal tract improves the gastric
retention time of the dosage form & thus, the absorption of drugs in-
creases by allowing its stay at the absorption site for a longer period
[36].
3.2.3. Calorie content
The rate of gastric emptying primarily depends on the caloric con-
tents of the ingested meal [37]. It does not differ for proteins, fats, car-
bohydrates as long as their caloric content is the same. Generally an
increase in acidity, osmolarity, and caloric value slows down gastric
emptying [38]. GRT can be increased between 4 and 10 h with a
meal that is high in proteins and fats.
3.2.4. Frequency of feed
The GRT can increase by over 400 min when successive meals are
given compared with a single meal due to the low frequency of MMC.
3.3. Patient related factors
3.3.1. Gender
Gastric emptying rate may differ in male & female. Generally the
gastric emptying in women was slower than in men [39].
3.3.2. Age
Elderly people, especially those over 70 years have a longer
gastroretentive time [40]. Thus gastric emptying time is slowed
down [39].
3.3.3. Posture
The effect of posture on GRT, found no signicant difference in the
mean GRT for individuals in upright, ambulatory and supine state. In
the upright position, the oating systems oated to the top of the gas-
tric contents and remained for a longer time, showing prolonged GRT.
But the non-oating units settled to the lower part of the stomach
and underwent faster emptying as a result of peristaltic contractions,
and the oating units remained away from the pylorus. However, in
supine position, the oating units are emptied faster than the non-
oating units of similar size.
3.3.4. Concomitant drug administration
Administration of drugs with impact on gastrointestinal transit
time for example drugs acting as anticholinergic agents (e.g. atropine,
propantheline), Opiates (e.g. codeine) and prokinetic agents (e.g.
metoclopramide, cisapride) can alter gastro retention of oral dosage
forms [37]. Anticholinergics like atropine and propantheline increase
gastric residence time. Drugs like metoclopramide and cisapride de-
crease gastric residence time.
 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
3.4. Disease state
In gastric ulcer, diabetes, and hypothyroidism there is an increase
in gastric residence time. In the case of hyperthyroidism and duodenal
ulcers there is a decrease in gastric residence time [41].
3.5. Volume of the GI uid
The resting volume of the stomach is 25 to 50 ml. The volume of
liquids administered affects the gastric emptying time. When the vol-
ume is large, the emptying is faster. Fluids taken at body temperature
leave the stomach faster than colder or warmer uids.
3.6. Effect of gastrointestinal uid
On comparison of the oating and non-oating units, it was con-
cluded that regardless of their sizes the oating units remained buoy-
ant on the gastric contents throughout their residence in the GIT,
while the non-oating units sink and remained in the lower part of
the stomach. Floating units away from the gastro-duodenal junction
were protected from the peristaltic waves during the digestive
phase while non-oating forms stayed close to the pylorus and
were subjected to propelling and retropelling waves of the digestive
phase [42].
4. Different gastroretentive forms
Many technological approaches have been made to develop a dos-
age form that can be retained in the stomach. The approaches that
have been proposed to increase the retention of an oral dosage form
in the upper part of the gastrointestinal tract are described in Fig. 5.
4.1. High-density systems/non-oating system
Gastric contents have a density close to water ( 1.004 g/cm 3).
These systems have density higher than the gastric content. A density
close to 2.5 g/cm 3 is necessary for signicant prolongation of gastric
residence time [43]. Barium sulfate, zinc oxide, iron powder, and
Fig. 5. Different approaches of the gastroretentive drug delivery system.
155
titanium dioxide are excipients used to formulate such type of dosage
form (Fig. 5a).
4.2. Low density system/oating system
Floating systems were rst described by Davis in 1968. Low densi-
ty system or oating drug delivery system has bulk density lower
than that of the gastric uid, and thus remain buoyant in the stomach
for a prolonged period (Fig. 5b). Floating drug delivery system is one
of the important approaches to achieve gastric retention to obtain
sufcient drug bioavailability [44]. This delivery system is desirable
for drugs with an absorption window in the stomach or in the
upper small intestine [45].
Based on the mechanism of buoyancy two distinctly different tech-
nologies, i.e. non-effervescent and effervescent systems have been uti-
lized for the development of the oating drug delivery system.
4.2.1. Non effervescent system
The non-effervescent oating drug delivery system is based on the
mechanism of swelling of polymer or bioadhesion to mucosal layer in
the GI tract. Non-effervescent oating dosage forms use a gel forming or
swellable cellulose type of hydrocolloids, polysaccharides, and matrix-
forming polymers like polycarbonate, polyacrylate, polymethacrylates,
and polystyrene. The formulation methods of such dosage forms involve
the mixing of the drug with a polymer, which swells in contact with the
gastric uid after oral administration and maintains a relative integrity
of shape and a bulk density is less than one within the outer gelatinous
barrier [46].
4.2.1.1. Single layer oating tablets. They are formulated by uniform
mixing of a drug with a gel-forming hydrocolloid, which swells in
contact with gastric uid and maintains specic gravity less than
one. They are formulated by blending of a drug with low-density en-
teric materials such as cellulose acetate phthalate and hydroxyl pro-
pyl methyl cellulose [47].
4.2.1.2. Bi-layer oating tablets. A bi-layer tablet contains two layers.
One is an immediate release layer which releases loading dose from
the system while the other is a sustained release layer which releases
dose by absorbing gastric uid, forming an impermeable colloidal gel
barrier on its surface, and maintains a specic gravity less than unity
and thereby remains buoyant in the stomach [47].
4.2.1.3. Hydrodynamically balanced systems. Seth and Tossounian [48]
were the rst to designate these hydrodynamically balanced systems.
These are single-unit dosage forms, containing one or more gel-
forming hydrophilic polymers. Hydroxypropylmethylcellulose (HPMC)
is the most common used excipient, although hydroxyethylcellulose
(HEC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose
(NaCMC), agar, carrageenan or alginic acid is also used [49,50]. The
polymer is mixed with a drug and usually administered in a gelatin cap-
sule. The capsule rapidly dissolves in the gastric uid, and hydration and
swelling of the surface polymers produce a oating mass. Madopar LPR,
based on HBS system was marketed during the 1980s [42,59].
4.2.1.4. Microballoons/hollow microspheres. Microballoons/hollow mi-
crospheres loaded with drugs in their other polymer were prepared
by simple solvent evaporation or solvent diffusion methods [56] to
prolong the gastric retention time (GRT) of the dosage form. Com-
monly used polymers to develop these systems are polycarbonate,
cellulose acetate, calcium alginate, Eudragit S, agar, low methoxylated
pectin etc. Buoyancy and drug release from dosage form are depen-
dent on quantity of polymers, the plasticizer polymer ratio and the
solvent used for formulation [51,52].
156 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
4.2.1.5. Alginate beads. Talukdar and Fassihi [53] developed a multiple-
unit oating system based on cross-linked beads. They were formu-
lated by using Ca 2+ and low methoxylated pectin (anionic polysac-
charide) and sodium alginate. In this approach, generally a sodium
alginate solution is dropped into an aqueous solution of calcium chlo-
ride and causes the precipitation of calcium alginate. These beads are
then separated and dried by air convection and freeze drying, leading
to the formulation of a porous system, which can maintain a oating
force for over 12 h. These beads improve gastric retention time (GRT)
more than 5.5 h [54].
4.2.1.6. Microporous compartment system. This approach is based on
the principle of the encapsulation of a drug reservoir inside a micro-
porous compartment with pores along its top and bottom walls
[55]. The peripheral walls of the device were completely sealed to
prevent any direct contact of the gastric surface with the undissolved
drug. In the stomach the oatation chamber containing entrapped air
causes the delivery system to oat in the gastric uid [24]. Gastric
uid enters through the aperture, dissolves the drug and causes the
dissolved drug for continuous transport across the intestine for drug
absorption.
4.2.2. Effervescent system
Effervescent oating drug delivery systems are the systems which
generate gas (CO2), thus reducing the density of the system, and re-
main buoyant in the stomach for a prolonged period of time and re-
lease the drug slowly at a desired rate. Effervescent systems utilize
gas (CO2) generating agents (e.g. sodium bicarbonate, citric acid or
tartaric acid) to achieve oatability. The optimal stoichiometric ratio
of citric acid & sodium bicarbonate for gas generation is reported to
be 0.76:1 [56].
4.2.2.1. Gas-generating systems. Floatability can also be achieved by
generation of gas bubbles. This system involves incorporation of matrix
with entrapment of liquid, which forms a gas at body temperature
[57,58]. The approach has been used for single and multiple unit sys-
tems. In single unit systems, such as capsules or tablets [60,61], efferves-
cent substances are incorporated in the hydrophilic polymer, and CO2
bubbles are trapped in the swollen matrix. Drug and excipients can be
formulated independently and the gas generating unit can be incorpo-
rated into any of the layers. Further renements involve coating the
matrix with a polymer which is permeable to water, but not to CO2
[62]. The main difculty of such formulation is to nd a good compro-
mise between elasticity, plasticity and permeability of the polymer. It
is essential that the units remain dispersed and suspended individually
in the gastric uid and not agglomerate into a mass oating at the top of
the stomach [63].
4.2.2.1.1. Intragastric single-layered oating tablet. They are formu-
lated by intimately mixing the CO2 generating components and drug
candidates within a tablet matrix [64].
4.2.2.1.2. Intragastric bi-layered oating tablets. Intra gastric
bi-layered oating tablets may be compressed which contain the
gas generating mechanism in one hydrocolloid containing sustained
release layer and immediate release layer [65].
4.2.2.1.3. Multiple-unit type of oating pills. The system consists of
sustained release pills as seeds surrounded by double layers. The
inner layer was an effervescent layer containing tartaric acid and so-
dium bicarbonate. The outer layer was a swellable membrane layer.
Moreover, the effervescent layer was divided into two sublayers to
avoid direct contact between these two gas generating agents. Sodi-
um bicarbonate was contained in the inner sublayer, while tartaric
acid was in the outer layer. When the system was immersed in a buff-
er system at 37 C, it sinks at once in the solution and forms swollen
pills, like balloons (density b 1 g/ml), which oat as they have lower
density. This lower density is due to generation and entrapment of
CO2 within this system [66].
4.2.2.2. Volatile liquid. The GRT of a drug delivery system can be
sustained by incorporating an inatable chamber, which contains a
liquid e.g. ether, cyclopentane, that gasies at body temperature to
cause the ination of the chamber in the stomach [67].
4.2.2.2.1. Inatable gastrointestinal delivery system. These systems
are fabricated by loading the inatable chamber with a drug reservoir,
which can be a drug, impregnated polymeric matrix, then encapsulat-
ed in a gelatin capsule. After oral administration, the capsule dissolves
to release the drug reservoir together with the inatable chamber.
The inatable chamber contains liquid ether that gasies at body
temperature to cause the chamber to inate in the stomach and re-
tains the drug reservoir compartment in the stomach. The drug was
continuously released from the reservoir into the gastric uid.
4.2.2.2.2. Intragastric osmotically controlled drug delivery system.
The osmotic pressure controlled oating systems consist of two com-
partments. 1st compartment is drug reservoir compartment which is
enclosed in a pressure responsive bag, which is impermeable to vapor
and liquid. 2nd is osmotically active compartment which contains an
osmotically active salt and is enclosed within a semi permeable hous-
ing. The gastric uid in the stomach is continuously absorbed through
the semi permeable membrane into the osmotically active compart-
ment to dissolve the osmotically component. The osmotic pressure
is then produced, which acts on the collapsible bag and in turn forces
the drug reservoir compartment to reduce its volume and activate the
release of drug candidates in the form of a solution through the deliv-
ery orice. The oating support is also made to contain a bioerodible
plug that erodes after a predicted time period to deate the support.
The drug delivery system is then emptied from the stomach [68,69].
4.3. Bioadhesive systems
Bioadhesive systems are those systems which bind to the gastric
epithelial cell surface which serve as a potential means of extending
the gastric retention of drug delivery system in the stomach by in-
creasing the intimacy and duration of contact of drug with the biolog-
ical membrane [70] (Fig. 5c). These systems permit a given drug
delivery system to be incorporated with a bioadhesive agent. A
bioadhesive substance is a natural or synthetic polymer that enables
a device to adhere to the stomach and capable of producing an inter-
action based on hydration mediated, receptor mediated or bonding
mediated adhesion with the biological membrane of the gastrointes-
tinal mucosa [71,72]. Some promising excipients that have been used
are carbopol, chitosan, polycarbophil, lectins etc.
4.4. Swelling systems
These are the dosage forms, which after swallowing, swell to an
extent that prevents their exit from the pylorus (Fig. 5d). As a result,
the dosage form retains in the stomach for a longer period of time.
These systems may be named as plug type systems. Sustained and
controlled drug release may be achieved by selection of polymer of
proper molecular weight and swelling of the polymer retards the
drug release. On coming in contact with gastric uid, the polymer im-
bibes water and swells [47]. The extensive swelling of these polymers
is due to the presence of physical/chemical cross-links in the hydro-
philic polymer network. These cross-links prevent the dissolution of
the polymer and hence maintain the physical integrity of the dosage
form.
4.5. Expandable systems
A dosage form in the stomach will withstand gastric transit if it is big-
ger than the pyloric sphincter. Thus, three congurations are required: a
small conguration for oral intake, an expanded gastroretentive form
and a nal small form enabling evacuation following drug release [54]
(Fig. 5e). Thus, gastroretentivity is improved by the combination of
 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
substantial dimension with high rigidity of dosage form to withstand
peristalsis and mechanical contractility of the stomach. Unfoldable and
swellable systems have been investigated and recently tried to develop
an effective gastroretentive drug delivery.
4.6. Superporous hydrogels
Super porous hydrogel are swellable systems that differ sufcient-
ly from the conventional types. Absorption of water by conventional
hydrogel is a very slow process and several hours may be needed to
reach an equilibrium state [73] during which premature evacuation
of the dosage form may occur. Superporous hydrogels have an aver-
age pore size > 100 m which swell to an equilibrium size within a
minute, due to rapid uptake of water by capillary wetting through nu-
merous interconnected open pores [74]. Moreover, they swell to a
large size (swelling ratio 100 or more) and are intended to have suf-
cient mechanical strength to withstand pressure by gastric contrac-
tion. This is achieved by co-formulation of a hydrophilic particulate
material, Ac-Di-Sol (croscarmellose sodium) [75,88].
4.7. Magnetic systems
This system is based on a simple idea that the dosage form con-
tains a small internal magnet, and a magnet placed on the abdomen
over the position of the stomach. Using an extracorporeal magnet,
gastric residence time of the dosage form can be enhanced for a
prolonged period of time [76,77].
4.8. Ion exchange resin system
Ion exchange resin system is a system which is formulated to have
gastroretentive properties. Ion exchange resin beads are loaded with
bicarbonate and a negatively charged drug is bound to the resin
(Fig. 5f). The resultant beads were then encapsulated in a semi-
permeable membrane to overcome the rapid loss of carbon dioxide.
Upon arrival in the acidic environment of the stomach, an exchange
of chloride and bicarbonate ions takes place. As a result of this reac-
tion carbon dioxide was released and trapped in the membrane
thereby carrying beads towards the top of gastric content and pro-
ducing a oating layer of resin beads in contrast to the uncoated
beads, which will sink quickly [26].
Various merits and demerits of different approaches of the GRDDS
are summarized in Table 1.
5. Raft forming system
5.1. General consideration
Various attempts have been made to retain the dosage form in the
stomach as a way of increasing the retention time. Among the various
attempts, the raft forming system is an advanced revolution in oral
controlled drug delivery. Raft forming systems have received much
attention for the delivery of the drug for gastrointestinal infections
and disorders.
The raft forming system is one of the approaches which involve
the formulation of effervescent oating liquid with in situ gelling
properties, which has been assessed for sustaining drug delivery
and targeting. Moreover, the gels formed in situ remained intact for
more than 48 h to facilitate sustained release of drugs [78].
The mechanism of the raft forming system involves the forma-
tion of continuous layer called a raft. The system involves the forma-
tion of a viscous cohesive gel in contact with gastric uids, wherein
each portion of the liquid swells forming a continuous layer called a
raft [79,80]. The layer of the gel oats on the gastric uid because it
has bulk density less than the gastric uid, as low density is created
by the formation of CO2. So the system remains buoyant in the
157
stomach without affecting the gastric emptying rate for a prolonged
period of time [41]. The gel formed from in situ gelling, being lighter
than gastric uid, oats over the stomach contents or adheres to the
gastric mucosa due to the presence of a bioadhesive nature of the
polymer and prevents the reux of gastric content into the esopha-
gus by acting as a barrier between the stomach and the esophagus
(Fig. 6). Thus it produces retention of dosage form and increases
gastric residence time resulting in prolonged drug delivery in gas-
trointestinal tract [87]. When the system is oating on the gastric
contents, the drug is released slowly at the desired rate from the
system. After release of the drug, the residual system is emptied
from the stomach. This results in an increased gastro retention
time and a better control of the uctuations in plasma drug concen-
tration [78].
5.2. The design of the raft forming system
The formulation of the raft forming system depends on the phys-
icochemical properties of the drug molecule, the diseased condition
for which treatment is required, the patient population and the mar-
keting preference. Physico-chemical factors include molecular
weight, lipophilicity and molecular charge; an anatomical and physi-
ological factor includes membrane transport and pH of tissue uid;
formulation factors include pH, gelation temperature, viscosity, os-
molarity, and spreadability [81].
To achieve the gastric retention of the dosage form, the dosage
form must be able to satisfy the following criteria. They are as follows:
The drug should be released slowly from the system.
The dosage form must be able to withstand the force exerted by
peristaltic waves in the stomach and the constant contractions,
grinding and churning moments.
Should maintain specic gravity lower than gastric contents
(1.0041.01 g/cm 3).
The dosage form must remain in the stomach for a prolonged period
of time.
Better patient compliance.
Easy for administration for the patient.
After the release of the drug the device should be easily evacuated
from the stomach.
5.3. Ingredient used in the formulation of the raft forming system
An appropriate candidate should be selected for the formula-
tion of controlled release gastroretentive formulation. Various in-
gredients used in the formulation of such system are gel forming
agent and alkaline bicarbonates or carbonates which are responsi-
ble for the formation of a less dense system which oat on the
gastric uids [82].
5.3.1. Drugs used for the raft forming system
Raft forming systems have received much attention for the deliv-
ery of antacids and drug delivery for gastrointestinal infections and
disorders. The raft forming system is the potential approach for
heart burn and esophagitis. This system is suitable for acid soluble
drugs that are poorly soluble or unstable in intestinal uids [87]. Var-
ious drugs that can be used for the raft forming system are summa-
rized in Table 2 with their category.
Thus the criteria of the drug to be considered for the selection of
the drug for gastro retention are as follows:
Drugs that are locally active in the stomach [83].
Drugs that have narrow absorption window in the gastrointestinal
tract [8,83].
Drug that are absorbed from the stomach and upper part of the
gastrointestinal tract.
158 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
Table 1
Merits and demerits of different approaches of the gastroretentive drug delivery system.
Approaches Detail
High density system Sinking systems that retained
at the bottom of the stomach.
In this system density of pellets/
tablets > density of stomach uid.
Low density system System causes buoyancy in
gastric uid. In this system
density of pellets/tablets
b density of stomach uid.
Swelling system These are the dosage forms,
which after swallowing, swell
to an extent that prevents their
exit from the pylorus. As a result,
the dosage form is retained in
the stomach for a longer period
of time.
Bioadhesive system These systems are used to localize
a delivery device within the
lumen and cavity of the body to
increase the drug absorption process
in a site-specic manner.
Expandable system Use of size-increasing concept for
gastroretention. This system is
capable of increasing in size
relative to the initial dimensions.
Magnetic system Dosage forms contain a small
internal magnet and a magnet
is placed in the abdomen over
the position of the stomach that
retains the dosage form in the
gastric region.
Ion-exchange resin Coated ion exchange resin beads
system are loaded with bicarbonate and
a negatively charged drug is
bound to the resin. The resultant
beads were then encapsulated in
a semi-permeable membrane to
overcome the rapid loss of
carbon dioxide.
Drugs that are unstable in the intestinal or colonic environment
[4,83].
Drugs that disturb normal colonic microbes [85,83,8,84].
Merits
These systems with a density of about
3 g/cm3 retained in the antrum part
of the stomach and are capable of
withstanding its peristaltic movements
and allow the release of drug for a
prolonged period of time.
Improves better patient compliance.
No risk of dose dumping.
Enhance the bioavailability of a drug.
Reduce the frequency of dosing.
This system oats on gastric uid and
causes release of the drug slowly for a
longer period of time.
The HBS are advantageous for drugs that
are absorbed through the stomach e.g.
ferrous salts and for drugs meant for local
action in the stomach and treatment of
peptic ulcer disease e.g. antacids.
This approach is most widely used.
Improves better patient compliance.
No risk of dose dumping.
Enhance the bioavailability of the drug.
Reduce the frequency of dosing.
Allow the release of drug for a prolonged
period of time.
Improves patient compliance.
No risk of dose dumping.
Enhance the bioavailability of the drug.
Reduce the frequency of dosing.
Dosage form is small enough to be
swallowed, and thus not cause gastric
obstruction either singly or by accumulation.
Increase in size prevents the system from
passing via the pylorus and provides for
its prolonged stay in the stomach.
Magnetic system serves as a potential means
of extending the gastric retention of the
drug in the stomach by increasing duration
of contact of system in the gastric region.
This system oats on the gastric uid due
to exchange of chloride and bicarbonate
ions which further causes release of carbon
dioxide. Thus the drug was released slowly
for a longer period of time.
Drugs that degrade in the colon.
Drugs that exhibit low solubility at high pH values (or are poorly
soluble at alkaline pH) [83,86].
Demerits Ref.
Technically difcult to manufacture [44,58]
such formulations with high amount
of drug (>50%) [44].
Technically also difcult to achieve
a density of about 2.8 g/cm3 [44].
Effectiveness of this system in human
beings was not observed and thus such
system has not been marketed.
Retention of high density systems in the
antrum part under the migrating waves
of the stomach is questionable.
Single unit low density system is associated [50,58,79]
with problems such as sticking together or
being obstructed in the gastrointestinal
tract, which may have a potential danger
of producing irritation.
Single unit low density system is unreliable
and non-reproducible in prolonging
gastric residence time in the stomach when
administered orally.
One drawback of hydrodynamically balanced
systems is that this system, being a matrix
formulation, consists of a blend of drug and
low-density polymers. The release kinetics of
the drug cannot be changed without changing
the oating properties of the dosage form and
vice versa.
Floating drug delivery systems require high
uid level in stomach to oat and work
effectively.
Swelling of the dosage form causes oating [44,58,79]
of the dosage form and thus the system
requires high uid level in the stomach for
the oating of the dosage form and to work
effectively.
The oating systems in patients with
achlorhydria can be questionable in case
of swellable systems, faster swelling
properties are required and complete
swelling of the system should be achieved
well before the gastric emptying time.
Bioadhesion is difcult to maintain due to [44,58]
rapid turnover of mucin in GIT.
Time consuming. [84]
Difculty in formulation.
Not most widely used.
Despite numerous reports about successful [44,76,77,79]
tests, the real applicability of such systems
is doubtful because the desired results can
be achieved only if the external magnet is to
be positioned with high degree of precision.
The external magnet must be positioned
with a degree of precision that might
compromise patient compliance.
Not better patient compliance.
Not most widely used.
Not most widely used. [80]
Time consuming.
Very expensive to formulate this system.
 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
Fig. 6. Schematic illustration of the barrier formed by a raft-forming system.
The criteria of the drug that are not suitable for gastric retention
are [4,47];
Drugs that have very limited acid solubility.
Drugs that suffer instability in the gastric environment.
Drugs intended for selective release in the colon.
5.3.2. Polymer used for formulation
Various polymers are employed in oating drug delivery systems so
as to target the delivery of the drug to a specic region in the gastroin-
testinal tract i.e. stomach. Various natural and synthetic polymers are
used in the formulation of the raft forming drug delivery system.
Natural polymer such as alginic acid, guar gum, gellan gum, xyloglucan,
pectin, chitosan etc. and synthetic polymer such as poly(DL lactic acid),
poly(DL-lactide-co-glycolide) and poly-caprolactone, HPMC etc. are
used for formulation development of the raft forming drug delivery
system [89].
A polymer used for in situ gels should have the following charac-
teristics [90]
It should be biocompatible.
It should have pseudo plastic behavior.
The polymer should be capable of increasing the viscosity with in-
creasing the shear rate.
5.3.2.1. Alginic acid. Alginic acid is a linear block copolymer polysaccha-
ride consisting of -D-mannuronic acid and -L-glucuronic acid resi-
dues joined by 1, 4-glycosidic linkages (Fig. 7). These are unbranched
polysaccharides found in brown seaweed and marine algae such as
Laminaria hyperborea, Ascophyllum nodosum and Macrocystis pyrifera
[91]. Many different alginate salts and derivatives are also commercially
available including sodium alginate, ammonium alginate, calcium algi-
nate, magnesium alginate, potassium alginate etc. Out of these, sodium
alginate is most commonly and widely used in the oating drug deliv-
ery systems. Alginic acid can be chosen for gastroretentive formulations,
Table 2
Drugs that can be used for the raft forming system.
Category Drugs
Antacids Aluminum hydroxide, aluminum phosphate, magnesium
silicate, magnesium hydroxide, calcium carbonate.
H2 receptor antagonist Cimetidine, ranitidine, loxatidine, famotidine, nizatidine
Proton pump inhibitor Omeprazole, lansoprazole, pantoprazole, rabeprazole,
esomeprazole
Anti-cholinergic Oxyphenonium, propantheline, telezepine, pirenzepine
Anti-helicobacter Amoxicillin, clarithromycin, tetracycline,
pylori drugs metronidazole, tinidazole, colloidal bismuth.
159
Fig. 7. Structure of alginic acid [92].
since it exhibits favorable biological properties such as biodegradability
and nontoxicity. Formulation containing alginic acid not only has the
ability to form gel, but also have its mucoadhesive properties. It is hy-
drophilic, nontoxic, biodegradable, and biocompatible.
Sodium alginate is practically insoluble in ethanol (95%), ether, and
chloroform and slowly soluble in water, forming viscous colloidal solu-
tion [92]. It was found that alginates form compact structure when
ionic radii of the cation are lower. Dilute aqueous solutions of alginates
form rm gels on addition of di and trivalent metal ions by a cooperative
process involving consecutive glucuronic residues in the -L-glucuronic
acid blocks of the alginate chain [93]. Thus sodium citrate is added in the
preparation to form complexation with the free Ca2+ ions and release
them only in the highly acidic environment of the stomach. The
formulation thus remains in liquid form until it reaches the stomach,
where gelation is instantaneous [94]. Sodium alginate has been
employed in the preparation of gels for the delivery of biomolecules
such as drugs, peptides and proteins [95].
5.3.2.2. Gellan gum. Gellan gum is an anionic deacetylated exocellular
polysaccharide with a tetrasaccharide repeating unit of one -L-
rhamnose, one -D-glucuronic acid and two -D-glucuronic acid resi-
dues. It is secreted by the Sphingomonas elodea (Pseudomonas elodea).
The chemical structure of the polysaccharide has a tetrasaccharide re-
peat unit consisting of two glucose (Glc) residues, one glucuronic acid
(GlcA) residue, and one rhamnose (Rha) residue (Fig. 8). These are
linked together to give a tetrasaccharide repeat unit [96].
Commercially gellan gum is available as Gelrite or Kelcogel. It
has the tendency of gelation which is temperature dependent or cation
induced. This gelation involves the formation of double helical junction
zones followed by aggregation of the double helical segments to form a
three-dimensional network by complexation with cations and hydro-
gen bonding with water [97].
The formulation consists of gellan solution with calcium chloride
and sodium citrate complex, and when administered orally the calci-
um ions are released in the acidic environment of the stomach lead-
ing to gelation of gellan thus forming a gel in situ. Thus gellan gum
undergoes gel formation due to change in temperature or due to pres-
ence of cations (e.g. Na +, K +, Ca 2+) [98101].
5.3.2.3. Xyloglucan. Xyloglucan is a plant based polysaccharide
obtained from seeds of tamarind. It is composed of (14)--D-glucan
backbone chain, which has (16)--D xylose branches that are par-
tially substituted by (12)--D-galactoxylose [96]. Xyloglucan is
composed of heptasaccharide, octasaccharide and nonasaccharide
oligomers, which differ in the number of galactose side chains
(Fig. 9). Although xyloglucan itself does not form gel, dilute solutions
of xyloglucan which has been partially degraded by galactosidase ex-
hibit a thermally reversible solgel transition on heating [102]. When
160 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
Fig. 8. Structure of gellan gum.
xyloglucan is partially degraded by -galactosidase, the resultant
product exhibits thermally reversible gelation by the lateral stacking
of the rod like chains. The solgel transition temperature varies
with the degree of galactose elimination. It forms thermally reversible
gels on warming to body temperature. Xyloglucan gels can be poten-
tially used for oral, intraperitoneal, ocular and rectal drug delivery
[103]. Xyloglucan has shown a very low gelation time of up to few mi-
nutes. Its potential application in oral delivery exploits the proposed
slow gelation time (several minutes) that would allow in situ gelation
in the stomach following the oral administration of chilled xyloglucan
solution [104].
5.3.2.4. Pectin. Pectin is a plant origin anionic polysaccharide
extracted from the cell wall of most plants. Pectins are linear
polymers mainly comprised of -(14)-linked D-galacturonic acid
residues interrupted by 1, 2-linked L-rhamnose residues (Fig. 10).
They have an average molecular weight of about 50,000 to about
180,000 [105].
It readily forms gels in an aqueous solution in the presence of di-
valent ions such as free calcium ions, which crosslink the
galacturonic acid chains in a manner described by egg-box model
[106]. Generally, calcium ion is required to produce the gels that
are suitable as vehicles for drug delivery [107]. The main advantage
of using pectin for these formulations is that it is water soluble, so
organic solvents are not necessary in the formulation. Divalent
cations present in the stomach, carry out the transition of pectin
to gel state when it is administered orally. Calcium ions in the
complexed form may be included in the formulation for the induc-
tion of pectin gelation [108]. Sodium citrate may be added to the
pectin solution to form a complex with most of calcium ions
added in the formulation. By this means, the formulation may be
maintained in a uid state (sol), until the breakdown of the complex
in the acidic environment of the stomach, where release of calcium
ions causes gelation to occur. The quantities of calcium and citrate
ions may be optimized to maintain the uidity of the formulation
before administration resulting in gelation, when the formulation
is administered in the stomach.
Calcium ions in the complexed form may be included in the for-
mulation for the induction of pectin gelation. Pectin is commercially
available as low methoxy (LM) pectin (degree of esterication
(DE) b 50%) and high methoxy (HM) pectin (DE > 50%) [109]. LM
Fig. 9. Backbone structure of Xyloglucan. Glc, Xyl, and Gal indicate -D-
glucanpyranosyl, -D-xylopyranosyl and -D-galactopyranosyl residues respectively
[105].
Fig. 10. Structure of pectin.
pectins form a gel in the presence of divalent ions such as Ca 2+, and
can also form a gel in the absence of Ca 2+ when the pH is below 3.3
[110].
5.3.2.5. Chitosan. Chitosan is a biodegradable, thermosensitive, poly-
cationic polymer. It is obtained by alkaline deacetylation of chitin.
Chitin is a natural component of shrimp and crab shell. Chitosan
molecule is a copolymer of N-acetyl-D-glucosamine and D-glucosamine
(Fig. 11).
Chitosan is a biocompatible, pH dependent cationic polymer, which
remains dissolved in aqueous solutions up to a pH of 6.2 [104]. Neutral-
ization of chitosan aqueous solution to a pH exceeding 6.2 leads to the
formation of a hydrated gel like precipitate. On addition of chitosan
granules in acidic media (pH 1.2) and neutral media (deionized dis-
tilled water) it immediately becomes buoyant in nature and provides
a controlled release of the drug.
5.3.2.6. Carbopol. Carbopol is a well known pH dependent polymer,
which remains in solution form at acidic pH but forms a low viscous
gel at alkaline pH. HPMC is used in combination with carbopol to
impart the viscosity to carbopol solution. Various water soluble poly-
mers such as carbopol systemhydroxypropylmethylcellulose sys-
tem, poly(methacrylic acid)poly(ethylene glycol) can come under
the category of pH-induced in-situ precipitating polymeric systems.
5.4. Approaches used for the formulation of the raft forming drug
delivery system
Raft forming drug delivery systems are a revolution in oral drug de-
livery. These systems are liquids at room temperature but undergo ge-
lation when comes in contact with body uids or change in pH. These
have a unique property of temperature dependent and cation-induced
gelation. Gelation involves formation of the double helical junction
zones followed by aggregation of the double helical segments which
form three dimensional networks by complexation with cations and
hydrogen bonding [89].
Different approaches based on their mechanisms used for trigger-
ing the raft formation in the GIT are as follows.
5.4.1. Raft formation based on physical mechanism
5.4.1.1. Swelling. Formation of a gel occurs when the liquid efferves-
cent system comes in contact with gastric uid. In situ formation
of gel occurs when materials absorb water from the surrounding
environment and expand to occur at the desired space. Swelling of
the polymer occurs by absorption of water which further causes
formation of the gel. Certain biodegradable lipid substance such as
myverol 1899 (glycerol mono-oleate), is a polar lipid that swells
 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
Fig. 11. Structure of chitosan.
in water to form lyotropic liquid crystalline phase structures. It
has some bioadhesive properties and can be degraded in-vivo by
enzymatic action [111].
5.4.1.2. Diffusion. Diffusion is the method which involves diffusion of a
solvent from polymer solution into surrounding tissue, which further
results in precipitation or solidication of polymer matrix. Solution of
polymer that can be used for such mechanism is N-methyl pyrrolidone
(NMP) [112].
5.4.2. Raft formation based on chemical mechanism
5.4.2.1. Ionic cross linking. There are various polysaccharides that un-
dergo phase transition in the presence of various ions. Polysaccha-
rides falling into the class of ion-sensitive ones are most widely
used [113]. Ion sensitive polysaccharides such as carrageenan,
gellan gum (Gelrite), pectin, and sodium alginate undergo phase
transition in the presence of various ions such as k +, Ca +, Mg +,
and Na +. Various polysaccharides undergo gelation in the presence
of various monovalent, divalent cations. Alginic acid undergoes ge-
lation in the presence of divalent/polyvalent cations like Ca 2 + due
to the interaction with guluronic acid block in alginate chains.
K-carrageenan forms rigid, brittle gels in response to small amount
of K +, i-carrageenan forms elastic gels mainly in the presence of
Ca 2 +. Gellan gum commercially available as Gelrite is an anionic
polysaccharide that undergoes in situ gelling in the presence of
mono- and divalent cations, including Ca 2 +, Mg 2 +, K + and Na +. Ge-
lation of the low-methoxy pectin can be caused by divalent cations,
especially Ca 2 + [114,115].
5.4.3. Raft formation based on physiological stimuli mechanism
5.4.3.1. pH dependent gelling. Formation of gel in the system also oc-
curs due to change in the pH of the medium. Various pH dependent
polymers are used which cause the formation of in situ gel in the
system. Various polymers such as PAA (Carbopol, carbomer) or its
derivatives, polyvinylacetal diethylaminoacetate (AEA), mixtures of
poly(methacrylic acid) (PMA) and poly(ethylene glycol) (PEG)
show change from sol to gel with change of pH [115]. Swelling of
hydrogel increases as the external pH increases in the case of weakly
acidic (anionic) groups, but decreases if polymer contains weakly
basic (cationic) groups. Mixtures of poly(methacrylic acid) (PMA)
and poly(ethylene glycol) (PEG) also have been used as a pH sensitive
system to achieve gelation [115]. pH sensitive polymer can be neutral
or ionic in nature. The anionic networks contain negatively charged
moieties, cationic networks contain positively charged moieties, and
neutral networks contain both positive and negatively charged
moieties. In the case of anionic polymeric network containing carbox-
ylic or sulphonic acid groups, ionization takes place, as the pH of
the external swelling medium rises above the pKa of that ionizable
moiety.
5.4.3.2. Temperature dependent gelling. These hydrogels are liquid at
room temperature (20 C25 C) and undergo gelation when in contact
161
with body uids (35 C37 C), due to an increase in temperature.
This approach exploits temperature-induced phase transition. Some
polymers undergo abrupt changes in solubility in response to increase
in environmental temperature (lower critical solution temperature,
LCST) [116,117]. At the LCST, hydrogen bonding between the polymer
and water becomes unfavorable, compared to polymerpolymer and
waterwater interactions, and an abrupt transition occurs as the solvated
macromolecule quickly dehydrates and changes to a more hydrophobic
structure [118]. Alternatively, some amphiphilic polymers that
self-assemble in solution, show micelle packing and gel formation be-
cause of polymerpolymer interactions when temperature is increased
[119]. Temperature-sensitive hydrogels are probably the most common-
ly studied class of environment-sensitive polymer systems in drug deliv-
ery research. Polymers such as pluronics (poly(ethylene oxide)
poly(propylene oxide)poly(ethylene oxide) (PEOPPOPEO Triblock),
polymer networks of poly(acrylic acid) (PAA) and polyacrylamide
(PAAm) or poly(acrylamide-co-butyl methacrylate) are commonly
used for temperature sensitive hydrogels formation [120].
A positive temperature-sensitive hydrogel has an upper critical
solution temperature (UCST), and such hydrogel contracts upon
cooling below the UCST. Polymer networks of poly(acrylic acid)
(PAA) and polyacrylamide (PAAm) or poly(acryl amide-co-butyl
methacrylate) have positive temperature dependence of swelling
[96].
5.5. Advantages of oating raft forming gastroretentive drug delivery
system over other gastroretentive drug delivery system
Raft forming system forms a low density viscous layer on gastric
contents and hence provides more effective surface area than a tab-
let. These lead to more drug release and improve bioavailability.
Floating obtained faster than the other oating dosage form.
Improve patient compliance by making a once a day therapy.
Improve therapeutic efcacy.
Easy to administer to a patient.
5.6. Limitation of oating raft forming gastroretentive drug delivery
system over other gastroretentive drug delivery system
These systems are formulated in the form of solution which is more
susceptible to stability problems. These are due to chemical degra-
dation (oxidation, hydrolysis, etc.) or microbial degradation.
The formulation must be stored properly because if the formulation
is not stored properly it may cause stability problem. This is due to
change in the pH of the system on prolonged storage or on storing
inappropriate temperature conditions.
Exposure of certain polymer to radiations (e.g. UV, Visible, electro-
magnetic, etc.) induces the formation of gel within the package.
5.7. Evaluation parameters of the raft forming system
5.7.1. In vitro evaluation parameters
5.7.1.1. Texture analysis. Texture analysis is done to determine the
rmness, consistency and cohesiveness of the formulation. This anal-
ysis mainly indicates the syringeability of sol so the formulation can
be easily administered in-vivo. Higher value of adhesiveness of gels
is needed to maintain an intimate contact with surfaces like tissues
[121,122].
5.7.1.2. Solgel transition and gelling time. Raft forming system is an
effervescent liquid which involves the formation of viscous cohesive
gel in contact with gastric uids. The solgel transition temperature
may be dened as the temperature at which the phase transition of
162 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
sol meniscus is rst noted when kept in a sample tube at a specic
temperature and then heated at a specied rate. Gel formation is
indicated by a lack of movement of meniscus on tilting the tube.
Gelling time is the time for rst detection of gelation as dened
above [96].
5.7.1.3. Gel strength. This is used to determine gelling property of pre-
pared formulation. This parameter can be evaluated using a rheome-
ter. In this test a specied amount of gel is prepared in a beaker, from
the sol form. Gel containing beaker is raised at a certain rate, then
pushing a probe of rheometer slowly through the gel. The changes
in the load on the probe can be measured as a function of depth of im-
mersion of the probe below the gel surface [115,128].
5.7.1.4. Viscosity and rheology. This is an important parameter to be
evaluated for the raft forming system. The viscosity and rheological
properties of the polymeric formulations, either in solution or in gel
made with articial tissue uid (depending upon the route of admin-
istrations) were determined with a different viscometer. The viscosity
can be determined with Brookeld rheometer or some other type of
viscometers such as Ostwald's viscometer. The viscosity of formula-
tions should be such that no difculties are envisaged during their
administration by the patient [123,128].
5.7.1.5. Drugexcipient interaction studyFourier transform infra-red
spectroscopy and thermal analysis. Fourier transform infra-red spec-
troscopy is performed to study compatibility of ingredients. During
the gelation process, the nature of interacting forces can be evaluat-
ed using this technique. This technique employs potassium bromide
pellet method. Thermo gravimetric analysis can also be conducted
for in situ forming polymeric systems to quantitate the percentage
of water in hydrogel. Differential scanning calorimetry can also be
used to observe if there are any changes in thermo grams as com-
pared with the pure ingredients used thus indicating the interac-
tions [124].
5.7.1.6. In-vitro drug release. Raft forming system is administered
orally, thus drug release study is carried out using a different method.
Any of the following method can be used to determine in-vitro
drug release.
The in-vitro drug release of the in situ raft forming system can be
carried in 0.1 N HCl from 0 to 8 h by USP type V (Paddle over-disk)
at 50 rpm. The dissolution medium used is 900 ml of simulated gas-
tric uid (0.1 mol l1 HCl, pH 1.2) and temperature is maintained
at 37 0.2 C. Ten ml of the formulation was placed into a Petri
dish (4.5 cm i.d.) which can be kept in the dissolution vessel and sim-
ulated gastric uid is carefully added to the vessel avoiding any distur-
bance of the Petri dish. At each time interval, a precisely measured
sample of the dissolution medium is pipette out and replenished
with fresh medium. Drug concentration in the aliquot can be deter-
mined spectrophotometrically. Each study will be conducted in tripli-
cate. The plot of % Cumulative drug release v/s time (h) can be plotted
[84].
The in-vitro drug release of the raft forming system is carried in 0.1 N
HCl from 0 to 8 h by USP type-II apparatus at 50 rpm. The dissolution
medium used is 900 ml of simulated gastric uid (0.1 mol l1 HCl,
pH 1.2) and temperature is maintained at 37 0.2 C.
The release rate of the drug from sustained release suspension can be
determined by slightly modifying USP dissolution testing apparatus I
by covering the basket with muslin cloth at 50 rpm. This speed was
slow enough to avoid the breaking of gelled formulation and is
maintaining the mild agitation conditions believed to exist in vivo.
The dissolution medium used is 900 ml of 0.1 N HCl, and tempera-
ture was maintained at 37 C. A sample (5 ml) of the solution is
withdrawn from the dissolution apparatus from 0 to 8 h of dissolu-
tion. The samples are ltered through a 0.45 m membrane lter
and analyzed [125].
The drug release studies are carried out by using the plastic dialysis
cell. The cell is made up of two half cells, donor compartment and a
receptor compartment. Both half cells are separated with the help
of a cellulose membrane. The sol form of the formulation is placed
in the donor compartment. The assembled cell is then shaken hori-
zontally in an incubator. The total volume of the receptor solution
can be removed at intervals and replaced with the fresh media. This
receptor solution is analyzed for the drug release using analytical
technique [87].
5.7.1.7. Floating/buoyancy test. It is determined in order to measure
the time taken by the dosage form to oat on the top of the dissolu-
tion medium, after it is placed in the medium [73]. Test is usually
performed in SGF (simulated gastric uid) which is maintained at
37 C. The time between introduction of dosage form and its buoyan-
cy on the simulated gastric uid and the time during which the dos-
age form remains buoyant were measured. The time for which the
dosage form continuously oats on the dissolution media is termed
as oating time. The time taken for dosage form to emerge on the sur-
face of the medium is called Floating Lag Time (FLT) or Buoyancy Lag
Time (BLT) and total duration of time by which dosage form remains
buoyant is called Total Floating Time (TFT) [73,125].
5.7.2. In-vivo evaluation test
5.7.2.1. Radiology and scintigraphy. It involves the use of radio-opaque
markers. Xray/Gamma Scintigraphy helps to locate dosage form in
the gastrointestinal tract (GIT), thus one can predict and correlate
the gastric emptying time and the passage of dosage form in the
GIT. Barium sulfate is widely used as Radio Opaque Marker. Here
the inclusion of a radioopaque material i.e. BaSO4 into a solid dosage
form enables it to be visualized by X-rays at different intervals to de-
termine gastric retention. Similarly inclusion of emission of radio-
nuclide in a formulation allows indirect external observation using a
scintiscanner. In case of scintigraphy, the rays emitted by the ra-
dionuclide are focused on a camera, which helps to monitor the loca-
tion of the dosage form in the GIT. 99Tc is widely used as the emitting
material [126].
5.7.2.2. Gastroscopy. Gastroscopy is peroral endoscopy used with ber
optics or video systems. Gastroscopy is used to inspect visually the ef-
fect of dosage form for prolongation in stomach. It can also give the
detailed evaluation of the gastroretentive drug delivery system [127].
5.7.2.3. Magnetic marker monitoring. In this technique, dosage form is
magnetically marked with incorporating iron powder inside the dos-
age form. Image of the dosage form can be taken by very sensitive
bio-magnetic measurement equipment. Advantage of this method is
that it is radiation less and thus not too much hazardous [127].
5.7.2.4. 13C octanoic acid breath test. 13C octanoic acid is incorporated
into the gastroretentive drug delivery system and the system is intro-
duced in the stomach. In the stomach due to chemical reaction,
octanoic acid liberates CO2 gas which comes out in breath. The impor-
tant carbon atom which will come in CO2 is replaced with 13C isotope.
So the time up to which 13CO2 gas is observed in breath can be con-
sidered as gastric retention time of the dosage form. As the dosage
form moves to the intestine, there is no reaction and no CO2 release.
So this method is cheaper than the other [127].
 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165 163

6. Marketed formulation of the raft forming system liquid is a thick suspension that on swallowing slides down the
esophagus into the stomach. It forms a barrier over the top of the
Various commercial formulations of the raft forming system are stomach contents preventing the acid from rising into the esopha-
tabulated in Table 3. gus [134,135].
Indeed, clinical studies have shown that Gaviscon is superior to
placebo, and equal to or signicantly better than traditional antacids
Table 3
Various marketed formulations of the raft forming system. for relieving heartburn symptoms. Alginate-based, raft-forming
formulations have been used to treat reux symptoms in infants &
Brand Active ingredient Company Delivery Reference
children and in the management of heartburn and reux during
name system
pregnancy. While Gaviscon is effective when used alone, it is com-
Liquid Aluminum GlaxosMithKline, Effervescent [129,131]
patible with, and does not interfere with the activity of antisecretory
Gaviscon hydroxide India. oating
(95 mg) and liquid
agents such as cimetidine. Even with the introduction of new
magnesium alginate antisecretory and promotility agents, alginate-rafting formulations
carbonate preparations. will continue to have a role in the treatment of heartburn and reux
(358 mg). symptoms. Their unique non-systemic mechanism of action pro-
Topalkan Aluminum and Pierre fabre Effervescent [130,131]
vides rapid and long-duration relief of heartburn and acid reux
magnesium drug, France. oating
mixture. liquid symptoms [135].
alginate
preparation.
Almagate Aluminum and Floating [42,130,131]
9. Conclusion
Flot-Coat magnesium dosage form.
mixture.
In conventional dosage forms, oral drug delivery of drugs with
narrow absorption window in gastrointestinal tract is often limited
by poor bioavailability due to incomplete drug release and short res-
7. Patented preparation idence time at the site of absorption. To overcome this drawback,
novel drug delivery system has been developed which leads to in-
Various patents on the preparation of the raft forming system are crease in oral absorption of these drugs.
tabulated in Table 4. The gastroretentive drug delivery system is a burgeoning eld in
which most of the researchers are developing various technological
approaches in order to produce the desired gastric retention. Various
Table 4
Various patented preparations of the raft forming system. gastric retention approaches are studied such as oating drug deliv-
ery systems, high density system, mucoadhesive system, expandable
Sr. no. US patent Formulations Reference
system, swelling system and ion exchange system each having their
1. US20050063980 Gastric raft composition [133] own advantages and disadvantages. Among the various approaches
2. US5360793 Rafting antacid formulation [133]
the raft forming system has emerged as an efcient means of enhanc-
3. US20020119941 In situ gel formation of pectin [132]
ing the bioavailability and controlling the delivery of many drugs. It
provides stomach specic drug release for longer duration which re-
mains buoyant on the gastric surface. As the system remains in the
8. Advances in raft forming approach stomach for longer duration, local action of the drug is increased
due to prolonged contact time with the gastric mucosa. Thus leads
Alginates are established among the most versatile biopolymers, to less frequent dosing and improved efciency of treatment. Raft
used in a wide range of applications. Alginate-based raft-forming for- forming system is not only helpful for sustained drug delivery but
mulations usually contain sodium or potassium bicarbonate; in the also convenient for pediatric and geriatric patients. This system is
presence of gastric acid, the bicarbonate is converted into carbon di- helpful as an alternative of oral solid dosage form with the advantages
oxide which entraps within the gel precipitate, converting it into of liquid dosage form. Sustained and prolonged release of the drug,
foam and oats on the surface of the gastric contents, like a raft on good stability and bioavailability characteristics make the raft
water. Both in vitro and in vivo studies have demonstrated that forming system very suitable candidate for gastric retention of the
alginate-based rafts can entrap carbon dioxide, as well as antacid drug. Thus the raft forming system promises to be the potential ap-
components contained in some formulations, thus providing a rela- proach for gastric retention drug delivery system.
tively pH-neutral barrier. The strength of the alginate raft is depen- Due to unpredictability of human GIT development of efcient
dent on several factors, including the amount of carbon dioxide GRDFs is a real challenge to pharmaceutical technology as the drug
generated and entrapped in the raft, the molecular properties of the delivery system must remain for a sufcient time in the stomach
alginate, and the presence of aluminum or calcium in the antacid which is not compatible with normal physiology.
components of the formulation. Raft formation occurs rapidly, often Some of the unresolved, critical issues related to the rational de-
within a few seconds of dosing; hence alginate-containing antacids velopment include;
are comparable to traditional antacids for speed of onset of relief.
Since the raft can be retained in the stomach for several hours, 1. The quantitative efciency of the oating delivery systems in the
alginate-based raft-forming formulations can additionally provide fasted and fed states.
longer-lasting relief than that of traditional antacids. 2. An increasing understanding of polymer behavior, the role of the
Alginate-based raft-forming formulations have been marketed polymer behavior and the role of the biological factors.
world-wide under various brand names, including Gaviscon [134]. 3. Nowadays, herbal drug delivery is the emerging eld in pharma-
Gaviscon is a thick creamy suspension that is available in two cy. The use of FDDS for herbal medicament is one of the areas of
avors. Peppermint and aniseed avors. It is quite pleasant to taste focus for the pharmaceutical research scientists. The scientists
but a lot of people cannot bear the taste of aniseed. Gaviscon Ad- will nd it a great opportunity to work on GI transit proles.
vance is an extra strength treatment for heartburn, esophagitis and This has given rise to new products with substantial benets to
gastro esophageal reux disease also known as GERD. The Gaviscon the patients.
164 V.D. Prajapati et al. / Journal of Controlled Release 168 (2013) 151165
Acknowledgment
The authors express their deep thanks to SSR College of Pharmacy
for providing the necessary environment and support of suitable library
information source.
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