through GIT. Thus, the idea of enhancing drug
absorption in the GIT pioneered the idea of development of Gastro retentive
drug delivery system.
Gastroretentive Drug Delivery System (GRDDS) [4-7]
One of the most feasible approaches for
achieving a prolonged and predictable drug delivery profile in the GI tract is
to control the gastric residence time i.e. Gastroretentive
Dosage Forms (GRDFs).Gastroretentive systems can
remain in the gastric region for several hours and hence significantly prolong
the gastric residence time of drugs. Prolonged gastric retention improves
bioavailability, reduces drug waste, and improves solubility for drugs that are
less soluble in a high pH environment. It has applications also for local drug
delivery to the stomach and proximal small intestines.
Requirements for Gastric Retention
Physiological factors in the stomach,
it must be noted that, to achieve gastric retention, the dosage form must
satisfy certain 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 the constant contractions and grinding and churning mechanisms. To function
as a gastric retention device, it must resist premature gastric emptying.
Furthermore, once its purpose has been served, the device should be removed
from the stomach with ease.
Need For Gastric Retention
·
Drugs that are absorbed from the proximal part of
the gastrointestinal tract (GIT).
·
Drugs that are less soluble or are degraded by the
alkaline pH they encounters at the lower part of GIT.
·
Drugs that are absorbed due to variable gastric
emptying time.
·
For local or sustained drug delivery to the stomach
and proximal Small intestine to treat certain conditions.
·
Particularly useful for the treatment of peptic
ulcers caused by H. Pylori Infections.
Approaches for GRDDS [8--10]
The main approaches used for gastro retentive drug delivery system
(GRDDS) are described below and are shown in fig 1.
1) High-density systems
These include
coated pallets, and have density greater than that of the stomach content
(1.004 gm. /cm3). This is accomplishing by coating the drug with a heavy inert
material such as barium sulphate, ZnO,
titanium dioxide. This formulation of high-density pellet is based on
assumption that heavy pellets might remain longer in the stomach, since they
are position in the lower part of the antrum.
2) Bioadhesive
systems
These systems
are used to localize a delivery device within the lumen and cavity of the body
in order to enhance site-specific drug absorption process. In this, bio
adhesive polymers are used that can be adhere to the epithelial surface of the
GIT.
3) Expandable systems
These systems
are also called as “Plug type system”, since they exhibit tendency to remain
logged in the pyloric sphincters as upon coming in contact with gastric fluid,
the polymer imbibes water and swells. These polymeric matrices remain in the
gastric cavity for several hours even in fed state. By selection of polymer
with the proper molecular weight and swelling properties controlled and
sustained drug release can be achieved.
Fig 1:-different
approaches for gastroretentive drug delivery system
1) Floating
systems
Floating systems
have a bulk density lower than the gastric fluids (<~1.004g/cm³), and thus
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 a desired rate from the system. After the
release of the drug, the residual system is emptied from the stomach.
Floating systems
include following approaches.
a) Effervescent
floating dosage forms
These are matrix
type of system prepared with the help of Swellable
polymers and various effervescent compounds, examples; sodium bicarbonate,
tartaric acid and citric acid. They are formulated in such a way that when in
contact with acidic gastric contents, CO2 is liberated and get
entrapped in swollen hydrocolloids, which provides buoyancy to the dosage form.
b) Non
effervescent dosage forms
Non effervescent
floating dosage form use a gel forming or swellable
cellulose type hydrocolloids, polysaccharides and matrix forming polymers.
After oral administration, this dosage form swells in contact with gastric
fluids attains a bulk density. The air entrapped within the swollen matrix
imparts buoyancy to the dosage form.
c) Raft
forming systems
Here, a gel
forming solution (example Sodium alginate solution containing carbonates or
bicarbonates) swells and forms a viscous cohesive gel containing entrapped CO2
bubbles in contact with gastric fluid.
d) Low
density systems
Gas-generating
systems have a lag time before floating on the stomach contents during which
the dosage form may undergo premature evacuation through the pyloric sphincter.
Low density systems (<1g/cm3) with immediate buoyancy have therefore been
developed. They are made of low density materials entrapping oil or air. Most
are multiple unit systems and are also called microballoons
because the low density core.
Gastroretentive
floating Microsphere [10-11]
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 µm. Due to its small
particle size, these are widely distributed throughout the gastrointestinal
tract which improves drug absorption and reduces side effects due to localized
build-up of irritating drugs against the gastrointestinal mucosa.
Suitable Drug
Candidates for Floating Microspheres [12]
In general,
appropriate candidates for GRDDS are molecules that have poor colonic
absorption but are characterized by better absorption properties at the upper
parts of the GIT.
a)
Narrow
absorption window in GI tract. E.g., Riboflavin and Levodopa.
b)
Primarily
absorbed from stomach and upper part of GIT, e.g., Calcium supplements, Chlordiazepoxide
and Scinnarazine.
c)
Drugs
that act locally in the stomach, e.g., Antacids and Misoprostol.
d)
Drugs
that degrade in the colon, e.g., Ranitidine HCl and Metronidazole.
e)
Drugs
that disturb normal colonic bacteria, e.g., Amoxicillin trihydrate.
Advantages of floating microspheres [13]
Recently, gastroretentive floating microspheres are gaining much more
attention among various other dosage forms. Various potential benefits of these
multi-particulate systems are presented in the following text.
a) Improves patient compliance by decreasing
dosing frequency.
b)
Bioavailability
enhances despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable
plasma drug concentration is maintained by continuous drug release.
c)
Gastric
retention time is increased because of buoyancy.
d)
Enhanced
absorption of drugs which solubilise only in stomach.
e)
Drug
releases in controlled manner for prolonged period.
f)
Site-specific
drug delivery to stomach can be achieved.
g)
Superior
to single unit floating dosage forms as such microspheres releases drug
uniformly and there is no risk of dose dumping.
h)
Avoidance
of gastric irritation, because of sustained release effect.
i)
Better
therapeutic effect of short half-life drugs can be achieved.
Limitations
of floating microspheres [13-14]
a)
Floating
microspheres require sufficiently high level of fluid in the stomach so that
the system can float and thus sufficient amount of water (200–250 ml) to be
taken together with floating microspheres.
b)
The
ability of drug to remain in the stomach depends upon the subject being
positioned upright.
c)
Floating
microspheres drug delivery systems are not suitable for the drugs that have
solubility or stability problems in the gastric fluid.
d)
Drug
like Nifedipine, which is well absorbed along the
entire GIT and which undergoes significant first pass metabolism, may not be a
desirable candidate for floating microspheres drug delivery systems since the
slow gastric emptying may lead to the reduced systemic bioavailability.
Applications
of floating microspheres [15]
Floating
microspheres offers several applications for drugs having poor bioavailability
because of the narrow absorption window in the upper part of the
gastrointestinal tract. It retains at the site of absorption and thus enhances
the bioavailability. These are summarized as follows.
1)
Sustained
drug delivery:
Hollow
microspheres of non-steroidal anti-inflammatory drugs are very effective for
controlled release as well as it reduces the major side effect of gastric
irritation; for example floating microspheres of Indomethacin
are quiet beneficial for rheumatic patients.
2)
Site-Specific
Drug Delivery:
Floating microspheress 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.
3)
Absorption
enhancement:
Drugs that have
poor bioavailability because of site specific absorption from the upper part of
the
Gastrointestinal
tract are potential candidates to be formulated as floating drug delivery
systems, thereby maximizing their absorption.
4)
Solubility
Enhancement:
Floating microspheress are especially effective in delivery of
sparingly soluble and insoluble drugs. It is known that as the solubility of a
drug decreases, the time available for drug dissolution becomes less adequate
and thus the transit time becomes a significant factor affecting drug
absorption. For weakly basic drugs that are poorly soluble at an alkaline pH,
hollow microspheres may avoid chance for solubility to become the rate-limiting
step in release by restricting such drugs to the stomach.
5)
As
carriers:
The floating microspheress can be used as carriers for drugs with
so-called absorption windows, these substances, for example antiviral,
antifungal and antibiotic agents (Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides
and Tetracyclines) are taken up only from very
specific sites of the GI mucosa.
Methods of Preparation of Floating Microspheres [16-18]
1) Solvent evaporation method:
This technique is widely employed by large number of pharmaceutical
industries to obtain the controlled release of drug. This approach involves the
emulsification of an organic solvent (usually methylene
chloride) containing dissolved polymer and dissolved/dispersed drug in an
excess amount of aqueous continuous phase, with the aid of an agitator. The
concentration of the emulsifier present in the aqueous phase affects the
particle size and shape. When the desired emulsion droplet size is formed, the
stirring rate is reduced and evaporation of the organic solvent is realized under
atmospheric or reduced pressure at an appropriate temperature. The subsequent evaporation of the dispersed phase solvent yields
solid polymeric microspheres entrapping the drug. The solid microparticles are recovered from the suspension by
filtration, centrifugation, or lyophilisation. For
emulsion solvent evaporation, there are basically two systems which include
oil-in-water (o/w) and oil-in-oil (o/o) or water-in-oil (w/o) type.
2) Oil-In-Water Emulsion Solvent Evaporation Method:
In this process,
both the drug and the polymer should be insoluble in water while water
immiscible solvent is required for the polymer. In this method, the polymer is
dissolved in an organic solvent such as dichloromethane, chloroform, or ethyl
acetate, either alone or in combination. The drug is either dissolved or
dispersed into polymer solution and this solution containing the drug is
emulsified into an aqueous phase to make an oil-in water emulsion by using a
surfactant or an emulsifying agent. After the formation of a stable emulsion,
the organic solvent is evaporated either by increasing the temperature under
pressure or by continuous stirring. Solvent removal from embryonic microspheres
determines the size and morphology of the microspheres. It has been reported
that the rapid removal of solvent from the embryonic microspheres leads to
polymer precipitation at the o/w interface. This leads to the formation of
cavity in microspheres, thus making them hollow to impart the floating
properties. Oil-in-water emulsion is widely used than water-in-oil due to
simplicity of the process and easy cleans up requirement for the final product.
The mechanism of the o/w emulsion solvent. Evaporation
method is shown in fig.2.
Figure 2: - Methods of
Preparation of floating microspheres. a) Ionotropic gelation method, b) o/w emulsion Solvent evaporation
method.
3) Oil-in-Oil
Emulsification Solvent Evaporation Method:
This oil-in-oil (sometimes referred as water-in-oil) emulsification
process is also known as non aqueous emulsification solvent evaporation. In
this technique, drug and polymers are co- dissolved at room temperature into
polar solvents such as ethanol, dichloromethane, acetonitrile
etc. with vigorous agitation to form uniform drug–polymer dispersion. This
solution is slowly poured into the dispersion medium consisting of light/heavy
liquid paraffin in the presence of oil soluble surfactant such as Span. The
system is stirred using an overhead propeller agitator at 500 revolutions per
minute (rpm) and room temperature over a period of 2–3 h to ensure complete
evaporation of the solvent. The liquid paraffin is decanted and the microparticles are separated by filtration through a Whatmann filter paper, washed thrice with n-hexane, air
dried for 24 h and subsequently stored in desiccator.
Span 60 is generally used which is non ionic surfactant. Span 60 has an HLB
value of 4.3 and acts as a droplet stabilizer and prevents coalescence of the
droplets by localizing at the interface between the dispersed phase and
dispersion medium.
4) Ionotropic Gelation Method:
In this method,
cross linking of the polyelectrolyte takes place in the presence of counter
ions to form gel matrix. This technique has been generally employed for the
encapsulation of large number of drugs. Polyelectrolyte such as sodium alginate
having a property of coating on the drug core and acts as release rate
retardant contains certain anions in their chemical structure. These anions
forms meshwork structure by combining with polyvalent cations
and induced gelation. Microspheres are prepared by
dropping drug loaded polymeric solution using syringe into the aqueous solution
of polyvalent cations as depicted in Figure. The cations diffuses into the drug loaded polymeric drops,
forming a three dimensional lattice of ionically
cross linked moiety. Microspheres formed left into the original solution for
sufficient time period for internal jellification and they are separated by
filtration. Natural polymers such as alginates can be used to improve drug
entrapment and are widely used in the development of floating microspheres.
Characterization of Floating Microspheres [14, 19]
Floating
microspheres are characterized by following parameters:
Particle size analysis:
Particle size of
floating microspheres is determined by using an optical microscopy and size
distribution is carried out by sieving method. This is useful in the
determination of mean particle size with the help of calibrated ocular
micrometer.
Micromeritics:
Microspheres can
be characterized for their micromeritic properties
such as angle of repose, compressibility index and Hausner’s
ratio.
Angle of Repose: Angle
of repose (θ) of the floating microspheres measures the resistance to
particles flow, and is calculated according to fixed funnel standing cone
method.
Where θ is
angle of repose, 2H/D is surface area of the free standing height of the
microspheres heap that is formed on a graph paper after making the microspheres
flow from glass funnel.
Compressibility index:
Also called as Carr’s index and is computed according to the following
equation.
Hausner’s ratio: Hausner’s ratio
of floating microspheres is determined by comparing the tapped density to the
fluff density using the equation.
Percentage yield:
Percentage yield
of floating microspheres is calculated by dividing actual weight of product to
total amount of all non-volatile components that are used in the preparation of
floating microspheres and is represented by following formula.
Drug entrapment efficiency
Estimation of
drug content in floating microspheres can be carried out by dissolving the
weighed amount of crushed microspheres in required quantity of 0.1 N HCl and analyzed spectrophotometrically at a particular
wavelength using the calibration curve. Each batch should be examined for drug
content in a triplicate manner. The entrapment efficiency of floating
microspheres is calculated by dividing the actual drug content by the
theoretical drug content of microspheres.
Surface morphology
Surface
characteristics of floating microspheres are analyzed using a scanning electron
microscopy (SEM). Samples are coated with gold dust under vacuum prior to
observation. Cross sections should be made in order to observe the core and
internal structure of the microspheres. These studies are useful in the
examination of internal and external morphology of floating microspheres.
In vitro Buoyancy studies
In vitro floating
tests can be performed in USP type II dissolution test apparatus by spreading
the floating microspheres on a simulated gastric fluid (pH 1.2) containing the
surfactant. The media is stirred at 100 rpm at 37± 0.5 ⁰C. After specific intervals of time, both the fractions of
microspheres (floating and settled microspheres) are collected and buoyancy of
the floating microspheres is determined by using formula.
Where, Qf and Qs
are the masses of floating and settled hollow microspheres, respectively.
In- vitro Drug Release
Studies
Release rate of
drug from hollow floating microspheres is determined using USP dissolution
apparatus type I or type II at 37± 0.5 ⁰C. The
dissolution test is carried out using 900 ml of 0.1 N HCl
dissolution medium at 100 rpm for the required period of time. At an
appropriate interval, specific volume of aliquots are withdrawn and replaced
with an equivalent volume of fresh dissolution medium to maintain the constant
volume of dissolution medium. The sample solutions are filtered through Whatman
filter paper and solutions are analyzed using UV spectrophotometer.
In-Vivo Studies
The in vivo
gastric retentivity of a floating dosage form is
usually determined by g-scintigraphy or roentgenography.
Factors to be
considered during formulation of floating microspheres [20-21]
Addition of
polymer solution
As reported
that, the high surface tension of water caused the solidification and aggregation
of polymer on the surface of aqueous phase. To minimize the contact of polymer
solution with the air-water interface, a new method of introducing the polymer
solution into aqueous phase was developed which involves the introduction of
the polymer solution through the glass tube in an aqueous phase without
contacting the surface of water. This method improved the yield of microspheres
and reduced the extent of aggregate formation.
Speed of
rotation
It is obvious
that the rotation speed of propeller affects yield and size distribution of
microspheres. As the rotation speed of propeller is increased, the average
particle size decreases, while maintaining its morphology.
Temperature
The temperature
of the dispersing medium is an important factor in the formation of
microspheres as it controls the evaporation rate of the solvents. At lower
temperature (100C), prepared microsphere has crushed and irregularly
shaped morphology. The shell of the microsphere turns translucent during the
process, due to the slower diffusion rate of ethanol and dichloromethane. At
higher temperatures (400C), the shell of the microsphere becomes
thin and it might be due to faster diffusion of alcohol in the droplet into
aqueous phase and evaporation of dichloromethane immediately after introducing
it into the medium.
Continuous
phase volume
In microspheres
preparation, when the continuous phase volume was Increase the yield and
entrapment efficiency was decreased due to increasing the partition of drug in
to the continuous phase.
Internal
phase volume (organic phase)
The Particle
size of the microspheres decreased with increasing internal phase volume. This
can be explained as in less amount of solvent, the polymer solution was more
viscous which produce larger droplet when poured in to the continuous phase, so
particle size was increased. Further the Entrapment efficiency of drug in
microspheres was decreased with increasing the internal phase volume. This may
due to the movement of drug particle from internal phase to continuous phase
was increased because of decreasing the viscosity of drug: polymer solution.
Drug: Polymer
ratio
Entrapment
efficiency of the drug in microspheres was increased with increasing drug:
polymer ratio because increased polymer amount provides more binding site for
the drug molecules. Particle size of the
microspheres was increased with increasing drug: polymer ratio. This can be
explained as when the drug: polymer ratio was increased the polymer solution
was more viscous which produce larger droplet when poured in to the continuous
phase.
Future
Potential
As sustained
release systems, floating dosage forms offer various potential advantages
evident from several recent publications. Drugs that have poor bioavailability
because their absorption is restricted to the upper GI tract can be delivered
efficiently thereby maximizing their absorption and improving their absolute
bioavailability.
CONCLUSION:
Though much
research has been conducted to develop sustained release delivery systems, very
few systems, which retained in the stomach for a long time, have been developed
so far. Gastro retentive floating microspheres have emerged as an efficient
means of enhancing the bioavailability and controlling delivery of many drugs
molecules that are poorly soluble or unstable in intestinal fluids and exhibit
absorption window, low bioavailability, and extensive first pass metabolism.
The control of gastro intestinal transit could be the focus of the next decade
and may result in new therapeutic possibilities with substantial benefits for
patient.