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					Floating Drug Delivery Systems:An
approach to Gastro retention
By - 01/15/2007
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       Latest Reviews
       Vol. 5 Issue 1
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Ms. Julan. U. Desai

Despite tremendous advancements in drug delivery the oral route remains
the preferred route of administration of therapeutic agents because of low
cost of therapy and ease of administration lead to high levels of patient
compliance.

.

But the issue of poor bioavailability (BA) of orally administered drugs is still a
challenging one, though extensive advancements in drug discovery process are made 1

Conventional oral dosage forms provide a specific drug concentration in systemic
circulation without offering any control over drug delivery. CRDFs or controlled release
drug delivery systems (CRDDS) provide drug release at a predetermined, predictable and
controlled rate. The de novo design of an oral controlled drug delivery system (DDS)
should be primarily aimed at achieving more predictable and increased bioavailability
(BA) of drugs.
A major constraint in oral CRDD is that not all drug candidates are absorbed uniformly
throughout the gastrointestinal tract. Some drugs are absorbed uniformly throughout the
gastrointestinal tract. Some drugs are absorbed in a particular portion of gastrointestinal
tract only or are absorbed to a different extent in various segments of gastrointestinal
tract. Such drugs are said to have an “ absorption window ”. Thus, only the drug
released in the region preceding and in close vicinity to the absorption window is
available for absorption. After crossing the absorption window, the released drug goes to
waste with negligible or no absorption. This phenomenon drastically decreases the time
available for drug absorption after it and limits the success of delivery system. These
considerations have led to the development of oral CRDFs possessing gastric retention
capabilities 2.

One of the most feasible approaches for achieving a prolonged and predictable drug
delivery profiles in gastrointestinal tract is to control the gastric residence time(GRT)
using gastroretentive dosage forms (GRDFs) that offer a new and better option for drug
therapy.

Dosage forms that can be retained in stomach are called gastroretentive drug delivery
systems ( GRDDS)3. GRDDS can improve the controlled delivery of drugs that have an
absorption window by continuously releasing the drug for a prolonged period of time
before it reaches its absorption site thus ensuring its optimal bioavailability.

2. Physiological Considerations

2.1 Stomach: The site for gastro retention

The stomach is situated in the left upper part of the abdominal cavity immediately under
the diaphragm. Its size varies according to the amount of distension: up to 1500 ml
following a meal; after food has emptied, a collapsed state is obtained with resting
volume of 25-50 ml. The stomach is anatomically divided into 3 parts, fundus, body and
antrum (or pylorus). The proximal stomach, made up of fundus and body regions serves
as a reservoir for ingested materials while the distal region (antrum) is the major site of
mixing motions, acting as a pump to accomplish gastric emptying.

2.2 Gastrointestinal motility & emptying of food

 The process of gastric emptying occurs both during fasting and fed states, however the
pattern of motility differs markedly in the two states. Two distinct patterns of
gastrointestinal motility and secretion exist corresponding to the fasted and fed states. As
a result the bioavailability of orally administered drugs will vary depending on the state
of feeding.

In the fasted state, it is characterized by an interdigestive series of electrical event and
cycle, both through the stomach and small intestine every 2-3 hrs. This activity is called
the interdigestive myoelectric cycle or Migrating motor complex (MMC) is often divided
into four consecutive phases: basal (Phase I) pre burst (Phase II), burst (Phase III), and
Phase IV intervals.

PHASE I the quiescent period, lasts from 30 to 60 mins and is characterized by a lack of
secretary, electrical and contractile activity. PHASE II , exhibits intermittent activity for
20-40 min, during which the contractile motions increase in frequency and size. Bile
enters the duodenum during this phase, whereas gastric mucus discharge occurs during
the latter part of phase II and throughout phase III. PHASE III is a short period of
intense large regular contractions, termed “housekeeper waves” that sweep off undigested
food and last 10-20 min. PHASE IV is the transition period of 0-5 mins between Phase
III & I.

The motor activity in the fed state is induced 5-10 mins 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 2-6 h, and more typically,
3-4 h, with phasic contractions similar to Phase II of MMC 4 .

When CRDDS are administered in the fasted state, the MMC may be in any of its phases,
which can significantly influence the total gastric residence time (GRT) and transit time
in gastrointestinal tract.

This assumes even more significance for drugs that have an absorption window because
it will affect the amount of time the dosage form spends in the region preceding and
around the window. The less time spent in that region, the lower the degree of absorption.
On the other hand, in the fed stomach the gastric retention time (GRT) of non
disintegrating dosage forms depends mostly on their size and composition and caloric
value of food.

2.3 Requirements for gastro retention

From the discussion of the physiological factors in stomach, to achieve gastro retention,
the dosage form must satisfy some requirements. One of the key issues is that the dosage
form must be able to withstand the forces caused by peristaltic waves in the stomach and
constant grinding and churning mechanisms. It must resist premature gastric emptying
and once the purpose has been served, it should be removed from the stomach with ease 5
.

2.4 Approaches to gastric retention

Over the last 3 decades, various approaches have been pursued to increase the retention
of an oral dosage form in the stomach. These systems include: Bioadhesive systems,
swelling and expanding systems, High density systems, Floating systems, Modified
systems 1 .
3. Floating Drug Delivery Systems

The concept of FDDS was described in the literature as early as 1962. Floating drug
delivery systems (FDDS) have a bulk density less than gastric fluids and so remain
buoyant in the stomach without affecting the gastric emptying rate for a prolonged period
of time.

While the system is floating on the gastric contents, the drug is released slowly at the
desired rate from the system. After release of drug, the residual system is emptied from
the stomach. This results in an increased GRT and a better control of fluctuations in
plasma drug concentration 6 .




Fig 2: The mechanism of floating systems

Formulation of this device must comply with the following criteria:

1. It must have sufficient structure to form a cohesive gel barrier.

2. It must maintain an overall specific gravity lower than that of gastric contents (1.004 –
1.010).

3. It should dissolve slowly enough to serve as a drug reservoir.
A list of drugs used in the development of FDDS thus far is given in Table 1:

List of drugs explored for various floating dosage forms 6

Dosage
                                                  Drugs
Forms
Microspheres      Aspirin, Ibuprofen, Tranilast
Granules          Diclofenac sodium, Indomethacin, Prednisolone
Capsules          Diazepam, Furosemide, L-Dopa and Benserazide
Tablets / pills   Amoxycillin Trihydrate, Ampicillin, Diltiazem, p -Aminobenzoic acid,
                  Riboflavin-5’-phosphate, Theophylline, Verapamil HCl

Based on the mechanism of buoyancy, two distinctly different technologies, i.e.
noneffervescent and effervescent systems, have been utilized in the development of
FDDS.

3.1 Noneffervescent FDDS:

The most commonly used in noneffervescent FDDS are gel forming or highly swellable
cellulose type hydrocolloids, polysaccharides, and matrix forming polymers such as
polycarbonate, polyacrylate, polymethacrylate and polystyrene.

One of the approaches to the formulation of such floating dosage forms involves intimate
mixing of drug with a gel forming hydrocolloid, which swells in contact with gastric fluid
after oral administration and maintains a relative integrity of shape and a bulk density of
less than unity within the outer gelatinous barrier. The air trapped by the swollen polymer
confers buoyancy to these dosage forms. In addition, the gel structure acts as a reservoir
for sustained drug release since the drug is slowly released by a controlled diffusion
through the gelatinous barrier.

Sheth and Tossounian 7 postulated that when such dosage forms come in contact with an
aqueous medium, the hydrocolloid starts to hydrate by first forming a gel at the surface of
the dosage form. The resultant gel structure then controls the rate of diffusion of solvent-
in and drug-out of the dosage form. As the exterior surface of the dosage form goes into
solution, the gel layer is maintained by the immediate adjacent hydrocolloid layer
becoming hydrated. As a result, the drug dissolves in and diffuses out with the diffusing
solvent, creating a ‘receding boundary’ within the gel structure.

3.2 Effervescent FDDS:

These buoyant delivery systems utilize matrices prepared with swellable polymers such
as Methocel ® or polysaccharides, e.g., Chitosan, and effervescent components, e.g.,
sodium bicarbonate and citric or tartaric acid or matrices containing chambers of liquid
that gasify at body temperature.
The matrices are fabricated so that upon arrival in the stomach, carbon dioxide is
liberated by the acidity of the gastric contents and is entrapped in the gellified
hydrocolloid. This produces an upward motion of the dosage form to float on the chyme.

Stockwell et al 8 prepared floating capsules by filling with a mixture of sodium alginate
and sodium bicarbonate. The systems were shown to float during in vitro tests as a result
of the generation of CO 2 that was trapped in the hydrating gel network on exposure to an
acidic environment.

The carbonates, in addition to imparting buoyancy to these formulations, provide the
initial alkaline microenvironment for polymers to gel. Moreover, the release of CO 2
helps to accelerate the hydration of the floating tablets, which is essential for the
formation of a bioadhesive hydrogel. This provides an additional mechanism
(‘bioadhesion’) for retaining the dosage form in the stomach, apart from floatation.

Floating dosage forms with an in situ gas generating mechanism are expected to have
grater buoyancy and improved drug release characteristics. However, the optimization of
the drug release may alter the buoyancy and, therefore, it is sometimes necessary to
separate the control of buoyancy from that of drug release kinetics during formulation
optimization.

Gerogiannis and co-workers 9 have described the floating and swelling characteristics of
commonly used excipients. From the results of resultant-weight measurements of various
excipients, these authors concluded that higher molecular weight polymers and slower
rates of polymer hydration are usually associated with enhanced floating behavior.
Hence, the selection of high molecular weight and less hydrophilic grades of polymers
seems to improve floating characteristics.

3.3 In vitro and In vivo evaluation:

The various parameters that need to be evaluated for their effects on GRT of buoyant
formulations can mainly be categorized into following different classes:

Galenic parameters: Diametral size, flexibility and density of matrices.

Control parameters: Floating time, dissolution, specific gravity, content uniformity and
hardness and friability (if tablets).

Geometrical parameters: Shape.

Physiological parameters: Age, sex, posture, food.

The test for buoyancy and in vitro drug release studies are usually carried out in
simulated gastric and intestinal fluids maintained at 37°C. In practice, floating time is
determined by using the USP disintegration apparatus containing 900ml of 0.1N HCl as a
testing medium maintained at 37°C. The time required to float the HBS dosage form is
noted as floating or floatation time 1 .

Dissolution tests are performed using the USP dissolution apparatus. Samples are
withdrawn periodically from the dissolution medium, replenished with the same volume
of fresh medium each time, and then analyzed for their drug contents after an appropriate
dilution.

The specific gravity of FDDS can be determined by the displacement method using
analytical grade benzene as a displacing medium. The initial (dry state) bulk density of
the dosage form and the changes in floating strength with time should be characterized
prior to in vivo comparison between floating (F) and nonfloating (NF) units. Further, the
optimization of floating formulations should be realized in terms of stability and
durability of the floating forces produced, thereby avoiding variations in floating
capability that might occur during in vivo studies.

Resultant weight test: An in vitro measuring apparatus has been conceived to determine
the real floating capabilities of buoyant dosage forms as a function of time. It operates by
measuring the force equivalent to the force F required to keep the object totally
submerged in the fluid 10 .

This force determines the resultant weight of the object when immersed and may be used
to quantify its floating or nonfloating capabilities. The magnitude and direction of the
force and the resultant weight corresponds to the vectorial sum of buoyancy ( F bouy ) and
gravity ( F grav ) forces acting on the object as shown in the equation

F = F buoy – F grav

F = d f gV – d s gV = (d f - d s ) gV

F = (df – M / V) gV

in which F is the total vertical force (resultant weight of the object), g is acceleration due
to gravity, d f is the fluid density, d s is the object density, M is the object mass, and V is
the volume of the object .By convention, a positive resultant weight signifies that the
force F is exerted upward and that the object is able to float, whereas a negative resultant
weight means that the force F acts downward and that the object sinks. (Figure 3) 1 .
Fig 3: Effect of resultant weight during buoyancy on the floating tendency of
FDDS.

The crossing of the zero base line by the resultant weight curve from positive toward
negative values indicates a transition of the dosage form from floating to nonfloating
conditions. The intersection of lines on a time axis corresponds to the floating time of the
dosage form.

The in vivo gastric retentivity of a floating dosage form is usually determined by gamma
scintigraphy or roentgenography. Studies are done both under fasted and fed conditions
using F and NF (control) dosage forms. It is also important that both dosage forms are
non disintegrating units, and human subjects are young and healthy.

3.4 Advantages 11 :

Sustained drug delivery:

As mentioned earlier, drug absorption from oral controlled release (CR) dosage forms is
often limited by the short GRT available for absorption.

However, HBS type dosage forms can retain in the stomach for several hours and
therefore, significantly prolong the GRT of numerous drugs. .

These special dosage forms are light, relatively large in size, and do not easily pass
through pylorus, which has an opening of approx. 0.1– 1.9 cms.

Site specific drug delivery

A floating dosage form is a feasible approach especially for drugs which have limited
absorption sites in upper small intestine.
The controlled, slow delivery of drug to the stomach provides sufficient local therapeutic
levels and limits the systemic exposure to the drug. This reduces side effects that are
caused by the drug in the blood circulation. In addition the prolonged gastric availability
from a site directed delivery system may also reduce the dosing frequency.

The eradication of Helicobacter pylori requires the administration of various
medicaments several times a day, which often results in poor patient compliance. More
reliable therapy can be achieved by using GRDDS. Floating alginate beads have been
used for the sustained release of Amoxycillin trihydrate. Thus, it can be expected that the
topical delivery of antibiotic through a FDDS may result in complete removal of the
organisms in the fundal area due to bactericidal drug levels being reached in this area,
and might lead to better treatment of peptic ulcer.

Pharmacokinetic advantages

As sustained release systems, floating dosage forms offer various potential advantages.
Drugs that have poor bioavailability because their absorption is limited to upper GI tract
can be delivered efficiently thereby maximizing their absorption and improving their
absolute bioavalabilities.

Floating dosage forms with SR characteristics can also be expected to reduce the
variability in transit performance. In addition, it might provide a beneficial strategy for
gastric and duodenal cancer treatment.

The concept of FDDS has also been utilized in the development of various anti- reflux
formulations. Floating systems are particularly useful for acid soluble drugs, drugs poorly
soluble or unstable in intestinal fluids, and those which may undergo abrupt changes in
their pH dependent solubility due to food, age and disease states.

3.5 Limitations:

· They require a sufficiently high level of fluids in the stomach for the drug delivery
buoyancy, to float therein and to work efficiently.

· Floating systems are not feasible for those drugs that have solubility or stability
problems in gastric fluid.

· Drugs such as Nifedipine, which is well absorbed along the entire GI tract and which
undergoes significant first- pass metabolism, may not be desirable candidates for FDDS
since the slow gastric emptying may lead to reduced systemic bioavailability.

· Also there are limitations to the applicability of FDDS for drugs that are irritant to
gastric mucosa.

4.Conclusion
Dosage forms with a prolonged GRT will bring about new and important therapeutic
options. They will significantly extend the period of time over which drugs may be
released and thus prolong dosing intervals and increase patient compliance beyond the
compliance level of existing CRDFs. Many of the “Once-a-day” formulations will be
replaced by products with release and absorption phases of approximately 24 hrs. Also,
GRDFs will greatly improve the pharmacotherapy of the stomach itself through local
drug release leading to high drug concentrations at gastric mucosa which are sustained
over a large period. Finally, GRDFs will be used as carriers of drugs with the “absorption
window”.

References

1. Chawla G., Gupta P., Koradia V., Bansal A. K., Gastro retention: A means to address
regional variability in intestinal drug absorption. Pharm.Tech. 2003, 50 – 68.

2. Rouge N., Buri P. & Doelkar E., Drug absorption site in t gastrointestinal tract tract
and dosage forms for site specific delivery. Int.J.Pharm. 1996, 136(1), 117 – 139.

3. Cremer K., Drug delivery: Gastro- remaining dosage forms. Pharm.J. 1997, 259, 108.

4. Grubel P. et al, Gastric emptying of non-digestible solids in the fasted dog.
J.Pharm.Sci. 1987, 76, 117 – 122.

5. Garg S., & Sharma S., Gastro retentive drug delivery systems. Drug Delivery
oral.2003, 160 – 166.

6. Singh B., Kim K., Floating drug delivery systems: an approach to oral controlled drug
delivery via gastric retention. J.Control.release 2000, 63, 235 – 259.

7. Sheth P. R., & Tossounian J., The hydrodynamically balanced system (HBS): a novel
drug delivery system for oral use. Drug Dev.Ind.Pharm. 1984, 10, 313 – 339.

8. Stockwell A.F., Davis S.S., Walker S.E., In-vitro evaluation of alginate gel systems.
J.Control.release 1986, 3, 167 – 175.

9. Stockwell A.F., Davis S.S., Walker S.E., In-vitro evaluation of alginate gel systems.
J.Control.release 1986, 3, 167 – 175.

10.Timmermanns J., Moes A., How well do floating dosage forms float? Int.J.Pharm.
1990, 62(3), 207 – 216.

11. Yeole P. G., Khan S., Patel V. F., Floating drug delivery systems: Need and
development. Indian.J.Pharm.Sci. 2005, 67(3), 265 – 272.

				
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