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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
Fgravity
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.
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.
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.