A Brief
Review on Gastro Retentive System
Dahake MN, Wattamwar PP, Bongirwar RA, Mohale DS, Bakal RL and Chandewar AV
P.Wadhwani
College of Pharmacy, Yavatmal (M.S.) India
ABSTRACT:
Oral delivery of drug is the most preferable route of
drug delivery due to ease of administration, patient compliance and flexibility in
formulation etc. However, it is a well accepted fact that it is difficult to
predict the real in vivo time
of release with solid, oral controlled release dosage forms. Various attempts
have been made to prolong the retention time of the dosage form in the stomach.
One such approach is development of
floating Microspheres involves preparation of a device that remains buoyant in the
stomach contents due to its lower density than that of the gastric fluids.Floating microspheres are gastro-retentive drug
delivery systems based on non-effervescent approach. These microspheres are
characteristically free flowing powders consisting of proteins or synthetic
polymers, ideally having a size less than 200 micrometer. Floating microspheres
are prepared by solvent diffusion and
evaporation methods to create the hollow inner core. Floating
microspheres are specially gaining attention due to their wide applicability in
the targeting of drugs to stomach.
KEYWORDS: Oral controlled release dosage
form, retention time, floating microsphere.
INTRODUCTION:
Oral delivery of drug is the most preferable route of
drug delivery due to ease of administration, patient compliance and flexibility in
formulation etc. However, it is a well accepted fact that it is difficult to
predict the real in vivo time
of release with solid, oral controlled release dosage forms. Various attempts
have been made to prolong the retention time of the dosage form in the stomach.
One such method is the preparation of a device that remains buoyant in the
stomach contents due to its lower density than that of the gastric fluids.
The uniform distribution of these multiple unit dosage
forms along the GIT could result in more reproducible drug absorption and
reduced risk of local irritation; this gave birth to oral controlled drug
delivery and led to development of Gastro-retentive floating microspheres1,2.
Floating drug delivery systems
(FDDSs) are expected to remain buoyant in a lasting way upon the gastric
contents and consequently to enhance the bioavailability of drugs. The various
buoyant preparations include hollow microspheres, granules, powders, tablets,
capsules, pills and laminated films. Floating microspheres are specially
gaining attention due to their wide applicability in the targeting of drugs to
stomach. These floating microspheres have the advantage that they remain
buoyant and distributed uniformly over the gastric fluid to avoid the vagaries
of gastric emptying and release the drug for prolonged period of time. The need for gastro retentive dosage forms (GRDFs) has
led to extensive efforts in both academia and industry towards the development
of such drug delivery systems. These efforts resulted in GRDFs that were
designed, in large part, based on the following approaches:
(a) Low density form of the
DF that causes buoyancy in gastric fluid3
(b) High density DF that is
retained in the bottom of the stomach4
(c) Bioadhesion
to stomach mucosa5
(d) Slowed motility of the
gastrointestinal tract by concomitant administration of drugs or pharmaceutical
excipients6
(e) Expansion by swelling or
unfolding to a large size which limits emptying of the DF through the pyloric
sphincter.7
Various attempts have been done to retain the dosage
form in the stomach as a way of increasing retention time:
1. Bio/Mucoadhesive Systems:
The term bioadhesion describe
materials that bind to the biological substrates, such as mucosal memberes. Adhesion of bioadhesive
drug delivery devices to the mucosal tissue offeres
the possibility of creating an intimate and prolonged contact at the site of
administration. This prolonged residence time can result in the enhanced
absorption and in combination with a controlled release of drug also improved
patient compliance by reducing the frequency of administration. The
epithelial adhesive properties of mucin have been
applied in the development of gastro retentive drug delivery systems 8, 9.
2. Floating Systems:
Floating systems are low-density systems that have
sufficient buoyancy to float over the gastric contents and remain in the
stomach for a prolonged period. While the system floats over the gastric
contents, the drug is released slowly at the desired rate, which results in
increased gastro-retention time and reduces fluctuation in plasma drug
concentration10,11,12.
3. Swelling Systems:
These are capable of swelling to a size that prevents
their passage through the pylorus; as a result, the dosage form is retained in
the stomach for a longer period of time. Upon coming in contact with gastric
fluid, the polymer imbibes water and swells.13,14
TYPES OF FLOATING DRUG
DELIVERY SYSTEM:
Floating systems
are classified as follows:
1. Effervescent
Systems
2. Non-Effervescent Systems
1. Effervescent Systems:
A. Volatile liquid containing systems:
The Gastric retention times of a
drug delivery system can be sustained by incorporating an inflatable chamber,
which contains a liquid e.g. ether, cyclopentane,
that gasifies at body temperature to cause the inflatation
of the chamber in the stomach. The device may also consist of a bioerodible plug made up of PVA, Polyethylene, etc. that
gradually dissolves causing the inflatable chamber to release gas and collapse
after a predetermined time to permit the spontaneous ejection of the inflatable
systems from the stomach15.
B. Gas-generating Systems:
These buoyant delivery systems utilize
effervescent reactions between carbonate/bicarbonate salts and citric/tartaric
acid to liberate CO2, which gets entrapped in the gellified hydrocolloid layer of the systems thus decreasing
its specific gravity and making it to float over chime.16
These buoyant systems utilize matrices
prepared with swellable polymers like methocel, polysaccharides like chitosan,
effervescent components like sodium bicarbonate, citric acid and tartaric acid
or chambers containing a liquid that gasifies at body temperature. The optimal stoichiometric ratio of citric acid and sodium bicarbonate
for gas generation is reported to be 0.76:1. The common approach for preparing
these systems involves resin beads loaded with bicarbonate and coated with ethyl
cellulose. The coating, which is insoluble but permeable, allows permeation of
water. Thus, carbon dioxide is released, causing the beads to float in the
stomach .Other approaches and materials that have been reported are highly swellable hydrocolloids and light mineral oils, a mixture
of sodium alginate and sodium bicarbonate, multiple unit floating pills that
generate carbon dioxide when ingested, floating minicapsules
with a core of sodium bicarbonate, lactose and polyvinyl pyrrolidone
coated with hydroxypropyl methylcellulose (HPMC), and
floating systems based on ion exchange resin technology, etc.
This type of system, after swallowing, swells
unrestrained via imbibition of gastric fluid to an
extent that it prevents their exit from the stomach. These systems may be
referred to as the ‘plug-type systems’ since they have a tendency to remain
lodged near the pyloric sphincter. One of the formulation methods of such
dosage forms involves the mixing of drug with a gel, which swells in contact
with gastric fluid after oral administration and maintains a relative integrity
of shape and a bulk density of less than one within the outer gelatinous
barrier. The air trapped by the swollen polymer confers buoyancy to these
dosage forms.
Hydrodymamically balance system (HBS) was first design by Sheth and Tossounian in 1975.
Such systems contains drug with gel forming hydrocolloids meant to remain
buoyant on stomach contents. This system incorporate a high level of one or
more gel forming highly swellable cellulose type
hydrocolloids e.g. HEC, HPMC, NaCMC, Polysacchacarides and matrix forming polymers such as polycarbophil, polyacrylates and
polystyrene, incorporated either in tablets or in capsules. On coming in
contact with gastric fluid, the hydrocolloid in the system hydrates and forms a
colloidal gel barrier around the gel surface. The air trapped by the swollen
polymer maintains a density less than unity and confers buoyancy to this dosage
forms14.
This technology is based on the encapsulation of drug
reservoir inside a microporous compartment with
aperture along its top and bottom wall.16 The peripheral walls of
the drug reservoir compartment are completely sealed to prevent any direct
contact of the gastric mucosal surface with the undissolved
drug. In stomach the floatation chamber containing entrapped air causes the
delivery system to float over the gastric contents. Gastric fluid enters
through the apertures, dissolves the drug, and carries the dissolve drug for
continuous transport across the intestine for absorption.
Multiple unit floating dosage forms have been developed
from freeze-dried calcium alginate.15 Spherical beads of
approximately 2.5 mm in diameter can be prepared by dropping a sodium alginate
solution in to aqueous solutions of calcium chloride, causing precipitation of
calcium alginate. The beads are then separated snap and frozen in liquid
nitrogen, and freeze dried at -40° for 24 h, leading to the formation of porous
system, which can maintain a floating force over 12 hour.
Hollow microspheres (microballons),
loaded with ibuprofen in their outer polymer shells were prepared by a novel
emulsion-solvent diffusion method. The ehanol:
dichloromethane solution of the drug and an enteric acrylic polymer was poured
in to an agitated aqueous solution of PVA that was thermally controlled at
40°.The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane
formed in internal cavity in microspheres of the polymer with drug. The microballons floated continuously over the surface of
acidic dissolution media containing surfactant for greater than 12 hour in
vitro.
Development of floating microsphere:
Floating
microspheres are gastro-retentive drug delivery systems based on
non-effervescent approach. Hollow microspheres are in strict sense, spherical
empty particles without core. These microspheres are characteristically free
flowing powders consisting of proteins or synthetic polymers, ideally having a
size less than 200 micrometer. As the system floats
over gastric contents, the drug is released slowly at desired rate resulting in
increased gastric retention. Solid
biodegradable microspheres incorporating a drug dispersed or dissolved
throughout particle matrix have the potential for controlled release of drugs 17,18
Diagram; floating microsphere
in GI tract
Mechanism of
Floating Microspheres:
When microspheres
come in contact with gastric fluid the gel formers, polysaccharides and
polymers hydrate to form a colloidal gel barrier that controls drug release.
As the exterior surface of the dosage form dissolves,
the gel layer is maintained by the hydration of the adjacent hydrocolloid
layer. The air trapped by the swollen polymer lowers the density and confers
buoyancy to the microspheres. However a minimal gastric content needed to allow
proper achievement of buoyancy18, 10, 11, 19.
Methods of
Preparation:
1.
Single emulsion technique: -
The natural polymers are dissolved or dispersed in the aqueous medium followed
by dispersion in non-aqueous medium e.g. oil.
In the second step cross linking of dispersed globule is carried out.
Cross linking can be achieved by means of heat or by using the chemical cross
linkers. Cross linking by heat is affected by adding the dispersion to
previously heated oil. Heat denaturation is however,
not suitable for thermo labile drugs.
2.
Double emulsion technique: -
Preparation involves formation of multiple emulsions of type w/o/w and is best
suited to water soluble drugs, peptides, proteins and vaccines. This method can
be use with both the natural as well as synthetic polymers.
3.
Polymerization technique:-
Polymerization techniques are classified as,
a.
Normal
polymerization
b.
Interfacial
polymerization
4.
Phase separation cocervation technique: - In this technique polymer
is first dissolved in the suitable solvent and the drug is dispersed by making
its aqueous solution, if hydrophilic or dissolved in a polymer solution itself,
if hydrophilic. Phase separation is then accomplished by changing the solution
conditions by using any of the method mentioned above.
5.
Spray drying and spray
congealing: - These methods are based on the drying of mist of polymer and drug
in the air. Depending upon the removal of the solvent or cooling of the
solution, the 2 processes are named spray drying and spray congealing
respectively. The polymer is first dissolved in suitable volatile organic
solvent such as dichloromethane, acetone, etc. The drug is then dispersed in
the in the polymer solution under high speed homogenization. This dispersion is
then atomized in stream of hot air. Atomization causes formation of small
droplets from which solvent evaporates leading the formation of microsphere.
6.
Solvent extraction:- This method is used for preparation of micro
particles, involves removal of organic phase by extraction of organic solvent.
This method involves water miscible solvent such as isopropanol.
And the organic phase is finally removed by extraction with water.17
Advantages:
1. Improves patient
compliance by decreasing dosing frequency.
2. Better
therapeutic effect of short half-life drugs can be achieved.
3. Gastric retention
time is increased
4. Drug releases in
controlled manner for prolonged period.
5. Site-specific
drug delivery to stomach can be achieved.
6. Avoidance of
gastric irritation, because of sustained release effect, floatability and
uniform release of drug through multi particulate system.
7. Enhanced bioavailability
Ex. The bioavailability of riboflavin Controlled release
(CR) gastro retentive drug formulation (GRDF) is significantly enhanced in
comparison to the administration of non-GRDF CR polymeric formulations. There
are several different processes, related to absorption and transit of the drug
in the gastrointestinal tract, that act concomitantly to influence the
magnitude of drug absorption.20
Applications:
1. FDDS can improve the pharmacotherapy of oral
formulations and provide high and sustained drug concentrations along the
gastric mucosa.
2. A floating dosage form is a feasible approach
especially for drugs which have absorption sites in the upper small intestine.
3. The concept of FDDS has also been utilized in the
development of various anti-reflux formulations.
4. Hollow microspheres can greatly improve the
pharmacotherapy of the stomach through local drug release, leading to high drug
concentrations at the gastric mucosa, thus eradicating Helicobacter pylori from the sub-mucosal
tissue of the stomach and making it possible to treat stomach and duodenal
ulcers, gastritis and oesophagitis.
Limitations:
1) Requirement of high level of fluid in the stomach
for the delivery system to float and work efficiently.
2) These systems also require the presence of food to
delay their gastric emptying.
CONCLUSION:
Floating
microspheres enable prolonged and continuous input of drugs to the upper part
of GI tract and improves the bioavailability of the medications that are
characterized by narrow absorption window. Ultimately floating microsphere
provides a means to utilize all pharmacokinetic and pharmacodynamics advantages
of controlled release dosage forms for such drugs. From the observations it may
be concluded that drug absorption in the gastrointestinal tract is a highly
variable process and prolonging gastric retention of the dosage form extends
the time for drug absorption. Thus, gastro retentive dosage form provides an
additional advantage for a drug that are primarily absorbed in the upper
segment of GI tract. Although there are number of difficulties to be worked out
to achieve prolonged gastric retention a large number of companies are focusing
towards commercializing this technique.
REFERENCES:
1.
Jain, N.K., “Controlled Novel Drug Delivery”, Ist Eds., CBS Publishers and Distributors,
2.
Chien Y.W., “ Controlled and Modulated Release Drug Delivery
Systems”, in Encyclopedia of Pharmaceutical Technology, J. Swarbrick,
J.C. Boylan, Eds., Marcel Dekker Inc., New York,
1990, pp. 280-285.
3.
Deshpande AA et al. Development of a novel
controlled-release system for gastric retention. Pharm
Res. 1997; 14: 815-819.
4.
5.
Lehr CM. Bioadhesion technologies for the
delivery of peptide and protein drugs to the gastrointestinal tract. Crit. Rev.
Ther. Drug Carrier Syst. 1994; 11: 119-160.
6.
Groning R, Heun G. Dosage forms
with controlled gastrointestinal passage studies on the absorption of nitrofurantion. Int J Pharm.
1989; 56: 111-116.
7.
Rouge N et al. Drug absorption sites in the gastrointestinal tract and
dosage forms for site specific delivery. Int J Pharm.
1996; 136: 117-139.
8.
Ikeda K, Murata K,
Kobayashi M, Noda K. Enhancement of bioavailability of dopamine via nasal route
in beagle dogs. Chem Pharm
Bull 1992;40:2155-2158.
9.
Hannah B. Noval bioadhesive formulation in
drug delivery .16-19.
10.
Chawla, G. et al., Pharm.Tech., 27(7): 50-51, 2003.
11.
Chickering, D.E. et al., Reactive Polymers, 1995, (25):
189-206.
12.
Seng CH.J Pharm Sci 1995;74(4):399-405.
13.
Singh BN, Kim KH.
J. Controlled Release 2000;63(1-2):235-259.
14.
Cremer K. Pharm. J
1997;19:(108):259.
15.
Whitehead L et al, Development of a gastroretentive dosage form. Eur.
J. Pharm. Sci. 1996; 4 (Suppl.): S 182.
16. Harrigan RM. Drug delivery device
for preventing contact of undissolved drug with the
stomach lining, US Patent 4, 055, 178,
17. Vyas, S.P. and Khar.,
“Targeted and Controlled Drug Delivery Novel Carrier System”, Ist Ed., CBS. pp. 417-54.
18.
Shiv Kr, H.G. et al, I.J.P.E., 38(4), Oct-Dec,2004.
19.
Soppimath, K.S. et al., T.M., Drug
20.
Klausner EA et al., Novel Levodopa
gastroretentive dosage form: in vivo evaluation in dogs. J. Controlled release. 2003; 88: 117-126.
Received on 30.11.2009
Accepted on 27.01.2010
© A&V Publication all right reserved
Research Journal of Pharmaceutical
Dosage Forms and Technology.
2(1): Jan. –Feb. 2010, 28-31