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Drug Delivery ORAL

Gastroretentive Drug Deliver y Systems

a report by
S a n j a y G a r g and S h r i n g i S h a r m a

Associate Professor and Senior Research Fellow, Department of Pharmaceutics,


National Institute of Pharmaceutical Education and Research (NIPER)

Sanjay Garg is Associate Professor Introduction nanoparticles, proteinoid microspheres and


in the Department of Pharmaceutics pharmacosomes, etc. Compared with other
of the National Institute of
Pharmaceutical Education and Oral delivery of drugs is by far the most preferable applications, the frequency of dosing may be the
Research (NIPER). His areas of route of drug delivery due to the ease of same, but the gastroretentive dosage forms will
research interest include novel
drug delivery systems, especially
administration, patient compliance and flexibility in alter beneficially the absorption profile of the active
osmotically controlled oral systems, formulation, etc. From immediate release to site- agent, thus enhancing its bioavailability. For
bioadhesive formulations and specific delivery, oral dosage forms have really example, a significant increase in the bioavailability
vaginal drug delivery systems.
Professor Garg is involved with progressed. However, it is a well-accepted fact that it is of furosemide from a floating dosage form (42.9%)
pharmaceutical project management difficult to predict the real in vivo time of release with has been reported, compared with commercially
and with regulatory affairs.
solid, oral controlled release dosage forms. Thus, drug available tablets (Lasix ® (33.4%)) and enteric
Shringi Sharma is currently working
absorption in the gastrointestinal (GI) tract may be very products (29.5%).
as Senior Research Fellow in the short and highly variable in certain circumstances.
Department of Pharmaceutics of GRDFs greatly improve the pharmacotherapy of the
NIPER. He completed his Masters
in pharmaceutics. It is evident from the recent scientific and patent stomach through local drug release, leading to high
literature that an increased interest in novel dosage drug concentrations at the gastric mucosa
forms that are retained in the stomach for a (eradicating Helicobacter pylori from the submucosal
prolonged and predictable period of time exists today tissue of the stomach), making it possible to treat
in academic and industrial research groups. One of stomach and duodenal ulcers, gastritis and
the most feasible approaches for achieving a oesophagitis, reduce the risk of gastric carcinoma and
prolonged and predictable drug delivery profile in administer non-systemic, controlled release antacid
the GI tract is to control the gastric residence time formulations (calcium carbonate).
(GRT). Dosage forms with a prolonged GRT, i.e.
gastroretentive dosage forms (GRDFs), will provide GRDFs can be used as carriers for drugs with
us with new and important therapeutic options. so-called absorption windows. These substances,
for example antiviral, antifungal and antibiotic
The Multifarious Uses of GRDFs agents (sulphonamides, quinolones, penicillins,
cephalosporins, aminoglycosides and tetracyclines,
GRDFs extend significantly the period of time over etc.), are taken up only from very specific sites of the
which the drugs may be released. Thus, they not GI mucosa. In addition, by continually supplying the
only prolong dosing intervals, but also increase drug to its most efficient site of absorption, the dosage
patient compliance beyond the level of existing forms allow for more effective oral use of peptide and
controlled release dosage forms. This application is protein drugs such as calcitonin, erythropoietin,
especially effective in delivery of sparingly soluble vasopressin, insulin, low-molecular-weight heparin,
and insoluble drugs. It is known that, as the solubility protease inhibitors and luteinising hormone-releasing
of a drug decreases, the time available for drug hormone analogues.
dissolution becomes less adequate and thus the transit
time becomes a significant factor affecting drug Mechanistic Aspects of GRDFS
absorption. To address this, oral administration of
sparingly soluble drugs is carried out frequently, Various attempts have been made to retain the
often several times per day. dosage form in the stomach as a way of increasing
the retention time. These attempts include
As a mechanism to override this problem, erodible, introducing floating dosage forms (gas-generating
gastroretentive dosage forms have been developed systems and swelling or expanding systems),
that provide continuous, controlled administration mucoadhesive systems, high-density systems,
of these drugs at the absorption site. In addition, modified shape systems, gastric-emptying delaying
these dosage forms are useful for delivering drugs devices and co-administration of gastric-emptying
160 incorporated into vesicles such as liposomes, delaying drugs. Among these, the floating dosage

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Figure 1: The Mechanism of Floating Systems

Fgravity

Swelling system RW +ve Gas-generating


system

Imbibition of GF GF CO2 released GF


provides F buoyancy
RW -ve
Fbuoyancy

a b c
GF = Gastric fluid

forms have been used most commonly. However, GRT of the unit can be expected to be very
most of these approaches are influenced by a short. However, in the fed state, MMC is delayed
number of factors that affect their efficacy as a and GRT is considerably longer;
gastroretentive system:1–3
• nature of meal – feeding of indigestible polymers
• density – GRT is a function of dosage form or fatty acid salts can change the motility pattern
buoyancy that is dependent on the density; of the stomach to a fed state, thus decreasing the
gastric emptying rate and prolonging drug release;
• size – dosage form units with a diameter of more
than 7.5mm are reported to have an increased • caloric content – GRT can be increased by four
GRT compared with those with a diameter of to 10 hours with a meal that is high in proteins
9.9mm; and fats;

• shape of dosage form – tetrahedron and ring- • frequency of feed – the GRT can increase by over
shaped devices with a flexural modulus of 48 400 minutes when successive meals are given
and 22.5 kilopounds per square inch (KSI) are compared with a single meal due to the low
reported to have better GRT ≈ 90% to 100% frequency of MMC;
retention at 24 hours compared with other
shapes; • gender – mean ambulatory GRT in males (3.4±0.6
hours) is less compared with their age and race-
• single or multiple unit formulation – multiple unit matched female counterparts (4.6±1.2 hours),
formulations show a more predictable release regardless of the weight, height and body surface);
profile and insignificant impairing of performance
due to failure of units, allow co-administration of • age – elderly people, especially those over 70,
units with different release profiles or containing have a significantly longer GRT;
incompatible substances and permit a larger
margin of safety against dosage form failure • posture – GRT can vary between supine and
compared with single unit dosage forms; upright ambulatory states of the patient;

• fed or unfed state – under fasting conditions, the • concomitant drug administration – anticholinergics
GI motility is characterised by periods of strong like atropine and propantheline, opiates like
motor activity or the migrating myoelectric codeine and prokinetic agents like metoclopramide
complex (MMC) that occurs every 1.5 to 2 hours. and cisapride; and
The MMC sweeps undigested material from the
stomach and, if the timing of administration of the • biological factors – diabetes and Crohn’s disease,
formulation coincides with that of the MMC, the etc.

1. B M Singh and K H Kim, “Floating drug delivery systems: an approach to controlled drug delivery via gastric retention”,
J. Control. Rel., 63 (2000), pp. 235–259.
2. J Timmermans and A J Moes, “Factors controlling the buoyancy and gastric retention capabilities of floating matrix capsules:
new data for reconsidering the controversy”, J. Pharm. Sci., 83 (1994), pp. 18–24.
3. P Mojaverian, P H Vlasses, P E Kellner and M L Rocci, Jr., “Effects of gender, posture, and age on gastric residence time
162 of an indigestible solid: pharmaceutical considerations”, Pharm. Res., 10 (1988), pp. 639–644.

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Types of System mixture of sodium alginate and sodium bicarbonate,


multiple unit floating pills that generate carbon dioxide
Floating Drug Delivery Systems1 when ingested, floating minicapsules with a core of
sodium bicarbonate, lactose and polyvinyl pyrrolidone
Floating drug delivery systems (FDDS) have a bulk coated with hydroxypropyl methylcellulose (HPMC),
density less than gastric fluids and so remain buoyant in and floating systems based on ion exchange resin
the stomach without affecting the gastric emptying rate technology, etc.
for a prolonged period of time. While the system is
floating on the gastric contents (see Figure 1a), the drug Non-effervescent Systems
is released slowly at the desired rate from the system.
After release of drug, the residual system is emptied This type of system, after swallowing, swells
from the stomach. This results in an increased GRT unrestrained via imbibition of gastric fluid to an
and a better control of the fluctuations in plasma drug extent that it prevents their exit from the stomach.
concentration. However, besides a minimal gastric These systems may be referred to as the ‘plug-type
content needed to allow the proper achievement of the systems’ since they have a tendency to remain lodged
buoyancy retention principle, a minimal level of near the pyloric sphincter. One of the formulation
floating force (F) is also required to keep the dosage methods of such dosage forms involves the mixing of
form reliably buoyant on the surface of the meal. To drug with a gel, which swells in contact with gastric
measure the floating force kinetics, a novel apparatus fluid after oral administration and maintains a relative
for determination of resultant weight (RW) has been integrity of shape and a bulk density of less than one
reported in the literature.4 The RW apparatus operates within the outer gelatinous barrier. The air trapped
by measuring continuously the force equivalent to F (as by the swollen polymer confers buoyancy to these
a function of time) that is required to maintain the dosage forms (see Figure 1a).
submerged object. The object floats better if RW is on
the higher positive side (see Figure 1b). This apparatus Other approaches reported in the literature are
helps in optimising FDDS with respect to stability and hydrodynamically balanced systems developed by
durability of floating forces produced in order to Sheth and Tossounian, which contain a mixture of
prevent the drawbacks of unforeseeable intragastric drug and hydrocolloids, sustained release capsules
buoyancy capability variations. containing cellulose derivatives like starch and a
higher fatty alcohol or fatty acid glyceride, bilayer
RW or F = F buoyancy - F gravity compressed capsules, multilayered flexible sheet-like
= (Df - Ds) gV, medicament devices, hollow microspheres of acrylic
resins, polystyrene floatable shells, single and multiple
where RW = total vertical force, Df = fluid density, unit devices with floatation chambers and
Ds = object density, V = volume and g = microporous compartments and buoyant controlled
acceleration due to gravity. release powder formulations, etc.

The FDDS can be divided into gas-generating and Recent developments include use of superporous
non-effervescent systems. hydrogels that expand dramatically (hundreds of
times their dehydrated form within a matter of
Gas-generating Systems seconds) when immersed in water. Oral drug
delivery formulations made from the gels would
These buoyant systems utilise matrices prepared with swell rapidly in the stomach, causing medications to
swellable polymers like methocel, polysaccharides like move more slowly from the stomach to the intestines
chitosan, effervescent components like sodium and be absorbed more efficiently by the body.
bicarbonate, citric acid and tartaric acid or chambers
containing a liquid that gasifies at body temperature. Drugs reported to be used in the formulation of
The optimal stoichiometric ratio of citric acid and floating dosage forms are floating microspheres (aspirin,
sodium bicarbonate for gas generation is reported to be griseofulvin, p-nitroaniline, ibuprofen, terfinadine and
0.76:1. The common approach for preparing these tranilast), floating granules (diclofenac sodium,
systems involves resin beads loaded with bicarbonate indomethacin and prednisolone), films (cinnarizine),
and coated with ethylcellulose. The coating, which is floating capsules (chlordiazepoxide hydrogen chloride,
insoluble but permeable, allows permeation of water. diazepam, furosemide, misoprostol, L-Dopa,
Thus, carbon dioxide is released, causing the beads to benserazide, ursodeoxycholic acid and pepstatin) and
float in the stomach (see Figure 1c). Other approaches floating tablets and pills (acetaminophen, acetylsalicylic
and materials that have been reported are highly acid, ampicillin, amoxycillin trihydrate, atenolol,
swellable hydrocolloids and light mineral oils, a diltiazem, fluorouracil, isosorbide mononitrate, para-

164 4. J Timmermans and A J Moes, “How well do floating dosage forms float?”, Int. J. Pharm., 62 (1990), pp. 207–216.

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aminobenzoic acid, piretamide, theophylline and mechanism for pellets that are small enough to be
verapimil hydrochloride, etc.). Excipients used most retained in the rugae or folds of the stomach body near
commonly in these systems include HPMC, the pyloric region, which is the part of the organ with
polyacrylate polymers, polyvinyl acetate, Carbopol®, the lowest position in an upright posture. Dense
agar, sodium alginate, calcium chloride, polyethylene pellets (approximately 3g/cm3) trapped in rugae also
oxide and polycarbonates. Some of the marketed tend to withstand the peristaltic movements of the
formulations are listed as follows: stomach wall. With pellets, the GI transit time can be
extended from an average of 5.8–25 hours, depending
• Valrelease® – floating capsule of diazepam; more on density than on diameter of the pellets,
• Madopar® – benserazide and L-Dopa although many conflicting reports stating otherwise
combination formulation; also abound in literature. Commonly used excipients
• Liquid Gaviscon® – floating liquid alginate are barium sulphate, zinc oxide, titanium dioxide and
preparations; iron powder, etc. These materials increase density by
• Topalkan® – aluminium – magnesium antacid up to 1.5–2.4g/cm-3. However, no successful high-
preparation; and density system has made it to the market.
• Almagate Flot-Coat® – antacid preparation.
Large Single-unit Dosage Forms
Bioadhesive Systems
These dosage forms are larger than the pyloric
Bioadhesive drug delivery systems (BDDS) are used to opening and so are retained in the stomach. There
localise a delivery device within the lumen to enhance are some drawbacks associated with this approach.
the drug absorption in a site-specific manner. This Permanent retention of rigid large-sized single-unit
approach involves the use of bioadhesive polymers, forms can cause bowel obstruction, intestinal
which can adhere to the epithelial surface in the adhesion and gastroplasty.
stomach. A microbalance-based system is reported for
measuring the forces of interaction between the GI Co-administration of Gastric-emptying
mucosa and the individual polymers, and the Cahn Delaying Drugs
Dynamic Contact Angle Analyzer has been used to
study the adherence.5 This concept of simultaneous administration of a drug
to delay gastric emptying together with a therapeutic
Gastric mucoadhesion does not tend to be strong drug has not received the favour of clinicians and
enough to impart to dosage forms the ability to resist regulatory agencies because of the questionable
the strong propulsion forces of the stomach wall. The benefit-to-risk ratio associated with these devices.
continuous production of mucous by the gastric
mucosa to replace the mucous that is lost through Evaluation of Gastroretentive Dosage
peristaltic contractions and the dilution of the Forms
stomach content also seems to limit the potential of
mucoadhesion as a gastroretentive force. Evaluation for gastroretention is carried out by means
of X-ray and/or gamma scintigraphic monitoring of
Some of the most promising excipients that have the dosage form transit in the GI tract. The modern
been used commonly in these systems include technique of gamma scintigraphy now makes it
polycarbophil, carbopol, lectins, chitosan, CMC and possible to follow the transit behaviour of dosage
gliadin, etc. Some investigators have tried out a forms in human volunteers in a non-invasive manner.
synergistic approach between floating and bioadhesion
systems. Other approaches reported include use of a Conclusion
novel adhesive material derived from the fimbriae
(especially Type 1) of bacteria or synthetic analogues Finally, while the control of drug release profiles has
combined with a drug to provide for attachment to the been a major aim of pharmaceutical research and
gut, thereby prolonging the transit time, a composition development in the past two decades, the control of
comprising an active ingredient and a material that acts GI transit profiles could be the focus of the next two
as a viscogenic agent (for example curdlan and/or a decades and might result in the availability of new
low-substituted hydroxypropylcellulose), etc. products with new therapeutic possibilities and
substantial benefits for patients. Soon, the so-called
High-density Systems ‘once-a-day’ formulations may be replaced by novel
gastroretentive products with release and absorption
Sedimentation has been employed as a retention phases of approximately 24 hours. ■

5. D E Chickering, J S Jacob and E Mathowitz, “Bioadhesive microspheres II: Characterisation and evaluation of bioadhesion
166 involving hard, bioerodible polymers and soft tissue”, Reactive Polymers, 25 (1995), pp. 189–206.

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