INTRODUCTION:
Oral
administration is the most convenient and common route of drug delivery to the systematic
circulation. Oral controlled release drug deliveries have recently been of increasing interest in
pharmaceutical field to achieve improved therapeutic activity. Such as ease of
dosing administration, patient compliance and flexibility in formulation.
Floating drug delivery system is one of the important approaches to achieve
gastric retention to obtain sufficient drug bioavailability2,3.
These system have a bulk density lower than gastric fluids and thus remain
buoyant in the stomach for a prolonged period of time, without affecting
the gastric emptying rate . Drugs that
are easily absorbed from gastrointestinal tract (GIT) and have short half-lives
are eliminate quickly from the systemic circulation. Frequent dosing of these
drugs is required to achieve suitable therapeutic activity 1,4. The
development of oral sustained-controlled release formulations is an attempt to
release the drug slowly into the gastrointestinal tract (GIT) and maintain an
effective drug concentration in the systemic circulation for a long time. After
oral administration, such a drug delivery would be retained in the stomach and
release the drug in a controlled manner, so that the drug could be supplied
continuously to its absorption sites in the gastrointestinal tract (GIT)3.
These
drug delivery systems suffer from mainly two adversities: the short gastric
retention time (GRT) and unpredictable short gastric emptying time (GET), which
can result in incomplete drug release from the dosage form in the absorption
zone (stomach or upper part of small intestine) leading to diminished efficacy
of administered dose4. To formulate a site-specific orally
administered controlled release dosage form, It is desirable to achieve a prolong
gastric residence time by the drug delivery. Prolonged gastric retention
improves bioavailability, increases the duration of drug release, reduces drug
waste, and improves the drug solubility that are less soluble in a high pH
environment. Also prolonged gastric retention time (GRT) in the stomach could
be advantageous for local action in the upper part of the small intestine e.g.
treatment of peptic ulcer, etc. Gastro retentive drug delivery is an approach
to prolong gastric residence time, thereby targeting site-specific drug release
in the upper gastrointestinal tract (GIT) for local or systemic effects. Over
the last few decades, several gastro retentive drug delivery approaches being
designed and developed, including: high density (sinking) systems that is
retained in the bottom of the stomach, low density (floating) systems that
causes buoyancy in gastric fluid6,8 mucoadhesive
systems that causes bioadhesion to stomach mucosa, un
foldable, extendible, or swellable systems which limits emptying of the dosage forms
through the pyloric sphincter of stomach12,13, super porous hydrogel systems , magnetic systems 20etc.
Conventional
oral dosage forms offer no control over drug delivery, leading to fluctuations
in plasma drug level. 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 microspheres 3,4.
Certain types of drugs can benefit from using gastric retentive devices. These
include:
·
Drugs acting locally in the stomach;
·
Drugs that are primarily absorbed in the stomach;
·
Drugs that are poorly soluble at an alkaline ph;
·
Drugs with a narrow window of absorption;
SITE SPECIFIC DRUG DELIVERY
Site
specific drug delivery using novel formulation designs, would improve local
therapy in GIT optimize systemic absorption and would minimize premature drug
degradation. The site-specific delivery by gastro-retentive systems aimed to
achieve local or improved site specific absorption. These systems are
expandable or swellble in nature. Stomach specific
antibiotic drug delivery for instance would be highly beneficial in the treatment of helicobacter pylori infection
in the peptic ulcer disease. Gastro retentive drug delivery is an approach to
prolong gastric residence time, thereby targeting site-specific drug release in
the upper gastrointestinal tract (GIT) for local or systemic effects.
These
systems are particularly advantageous for drugs that are specifically absorbed
from stomach or the proximal part of the small intestine, eg,
riboflavin and furosemide. Eg.
Furosemide is primarily absorbed from the stomach
followed by the duodenum. It has been reported that a monolithic floating
dosage form with prolonged gastric residence time was developed and the
bioavailability was increased. AUC obtained with the floating tablets was
approximately 1.8 times those of conventional furosemide
tablets23.
Drugs which have site-specific absorption in the stomach or upper parts
of the small intestine (furosemide,riboflavine-5-phosphate), drugs required to
exert local therapeutic action in the stomach (antacids, anti-H. pylori agents,
misoprostol), drugs unstable in the lower part of Gastrointestinal tract
(captopril), drugs insoluble in intestinal fluids (quinidine, diazepam), drugs
with variable bioavailability (satolol HCl) (James Swarbrick, 2002).
This property prompted the development of monolithic floating dosage
form for furosemide, which could prolong the GRT and thus its bioavailability
was increased recently, a bilayer. Floating capsule has been used to achieve
local delivery of misoprostol at the gastric mucosa level. This reduces the
side effects that are caused by the presence of drug in blood circulation or a
combination of intestinal and systemic exposure while maintaining its
anticancer efficacy.
BIOLOGICAL
ASPECTS OF GRDS
Physiology of Stomach
Figure 1: Diagram of human stomach
OBJECTIVES
·
To enhance bioavailability
·
To enhance first pass biotransformation
·
Sustained drug delivery reduced frequency of dosing
·
Site-specific drug delivery
·
Reduced fluctuation of drug concentration
·
To minimize adverse activity at the colon.
·
Absorption enhancement
Conventional
vs. Floating drug delivery system
FACTORS AFECTING THE FLOATING
·
Density, size and shape of the dosage form.
·
Concomitant ingestion of the food and its nature, caloric content
and frequency of intake.
·
Biological factor such as gender, posture, age, sleep, body
weight, physical activity and disease states (e.g. diabetes, crohn’s disease).
CLASSIFICATION
Floating
drug delivery systems (FDDS) have a bulk density less than gastric fluids and so
remain buoyant in the stomach without affecting 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 the fluctuations in plasma drug
concentration. FDDS can be divided into non-effervescent and gas-generating
system. Based on the mechanism of buoyancy, floating systems can be classified
into two distinct categories viz.
non-effervescent and effervescent systems18,19.
A. NON-EFFERVESCENT SYSTEMS
This
type of system, after swallowing, swells unrestrained via imbibition
of gastomach. One of the formulation methods of such
dosage forms involves the mixing of the 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.
a)
Colloidal gel barrier systems:
Hydro
dynamically balanced system (HBS) of this type contains drug with gel forming
or swellable cellulose type hydrocolloids,
polysaccharides and matrix forming polymers. They help prolonging the GI
residence time and maximize drug reaching its absorption site in the solution
form ready for absorption. The HBS must
comply with following three major criteria:
·
It must have sufficient structure to form cohesive gel barrier.
·
It must maintain an overall specific density lower than that of
gastric contents.
·
It should dissolve slowly enough to serve as reservoir for the
delivery system.
b) Micro
porous compartment system
This
technology is comprised of encapsulation of a drug reservoir inside a micro
porous compartment with pores along its top and bottom surfaces. The peripheral
walls of the drug reservoir compartment are completely sealed to prevent any
direct contact of gastric mucosal surface with undissolved
drug. In stomach, the floatation chamber containing. Entrapped air causes the
delivery system to float over the gastric contents. The coated granules
acquired floating ability from the air trapped in the pores of calcium silicate
when they were coated with a polymer.
c)
Alginate beads
Multiple
unit floating dosage forms have been developed from freeze-dried calcium
alginate. Spherical beads of approximately 2.5 mm in diameter were prepared by
dropping a sodium alginate solution into aqueous solution of calcium chloride,
causing a precipitation of calcium alginate.
d)
Hollow Microspheres
Hollow
microspheres (micro balloons), loaded with ibuprofen in their outer polymer
shells were prepared by novel emulsion solvent diffusion method. The ethanol:
dichloromethane solution of the drug and an enteric acrylic polymer were poured
into an agitated aqueous solution of PVA that was thermally controlled at 40oC.
The gas phase was generated in dispersed polymer droplet by evaporation of
dichloromethane and formed an internal cavity in micro sphere of polymer with
drug. These micro balloons floated
continuously over surface of acidic solution media that contained surfactant,
for greater than 12 hrs in vitro 11,13.
Figure 1.
Formulation of floating hollow microsphere or microballoon.
B. EFFERVESCENT SYSTEMS
A drug delivery system can be made to float
in the stomach by incorporating a floating chamber, which may be filled with
vacuum, air or inert gas. The gas in floating chamber can be introduced either
by volatilization of an organic solvent or by effervescent reaction between
organic acids and bicarbonates salts 16.
Figure 2. Effervescent (gas generating) systems
Figure
3. Drug release from effervescent (gas generating) systems.
a)
Gas generating systems
These
buoyant delivery systems utilize effervescent reaction between carbonate/
bicarbonate salts and citric/tartaric acid to liberate CO2 which gets entrapped
in the jellified hydrochloride layer of the system, thus decreasing its
specific gravity and making it float over chyme.
These tablets may be either single layered wherein the CO2 generating
components are intimately mixed within the tablet matrix or they may be bilayer in which the gas generating components are
compressed in one hydrocolloid containing layer, and the drug in outer layer
for sustained release effect.
b) Magnetic Systems
This
approach to enhance the gastric retention time (GRT) is based on the simple
principle that the dosage form contains a small internal magnet, and a magnet
placed on the abdomen over the position of the stomach. Although magnetic
system seems to woks, the external magnet must be positioned with a degree of
precision that might compromise patient compliance18.
MECHANISM
OF FLOATING SYSTEMS
Various
attempts have been made to retain the dosage form in the stomach as a way of
increasing the retention time. These attempts include introducing floating
dosage forms (gas-generating systems and swelling or expanding systems), mucoadhesive systems, high-density systems, modified shape
systems, gastric-emptying delaying devices and co-administration of
gastric-emptying delaying drugs. Among these, the floating dosage forms have
been most commonly used. 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 (Figure 1a), the drug is released
slowly at the desired rate from the system 19. After release of
drug, the residual system is emptied from the stomach. This results in an
increased GRT and a better control of the fluctuations in plasma drug
concentration. However, besides a minimal gastric content needed to allow the
proper achievement of the buoyancy retention principle, a minimal level of
floating force (F) is also required to keep the dosage form reliably buoyant on
the surface of the meal. To measure the floating force kinetics, a novel
apparatus for determination of resultant weight has been reported in the
literature. The apparatus operates by measuring continuously the force
equivalent to F (as a function of time) that is required to maintain the
submerged object. The object floats better if F is on the higher positive side
(Figure 1b). This apparatus helps in optimizing FDDS with respect to stability
and durability of floating forces to prevent the drawbacks of unforeseeable intragastric buoyancy capability variations
F = F
buoyancy - F gravity = (Df - Ds) gv---
(1)
Where,
F = total vertical force,
Df = fluid density,
Ds = object density,
v = volume
g = acceleration due to gravity.
Fig.3 1) Different layers a) Semi-permeable membrane, b)
Effervescent Layer c) Core pill layer
2)Mechanism of floatation via CO2 generation.
FORMULATION AND CHARACTRISATION
Floating microspheres are characterized by their micromeritic properties such as particle size, tapped
density, compressibility index, true density and flow properties including
angle of repose. The particle size is determined by optical microscopy, true
density is determined by liquid displacement method, tabbed density and
compressibility index are calculated by measuring the change in volume using a
bulk density apparatus, angle of repose is determined by fixed funnel method.
The hollow nature are microspheres is confirmed by scanning electron
microscopy.
Floating behavior of hollow microsphere is studied
in a dissolution test apparatus by spreading the microspheres on simulated
gastric fluid containing between 80 as a surfactant, the media is stirred and a
temperature of 370C is maintained throughout the study.
a) Particle size
The particle size was measured
using an optical microscope and the mean particle size was calculated
by measuring around 200
particles with the help of a calibrated ocular micrometer.
b)
Angle of repose
Angle
of repose (θ) of the floating microspheres, which measures the resistance
to particle flow, was determined by a fixed funnel method and calculated as
Tan
θ = 2 H/D
Where,
2 H/D is the surface area of the
free standing height of the microshperes heap
c)
Tapped density
The tapping method was used to
determine the tapped density and percentage compressibility index as follows.-
a) Tapped density = Mass of
floating microspheres / Volume of floating microspheres after tapping
b)
% Compressibility index = [1-V/VO] ×100
c) Where V and V0 are the volumes
of the sample after and before the standard tapping respectively.
d) The true density of floating
microspheres was determined by liquid displacement method using n-hexane as
solvent.
d) Porosity
Porosity
(e) of the floating microspheres was calculated using the following equation22.
e =
[1-PP/PT] × 100
Where
Pt and Pp are the true density and tapped density respectively.
e)
Foating behavior
Buoyancy (%) = W f ( W f + Ws) ×100 Micro particles
Where,
W f=weights of floating and Ws= settled
micro particles
METHAD OF
PREPARATION OF FLOATING DRUG DILIVAARY SYSTEM
A)
SOLVENT
EVAPORATION METHOD
Figure
3: Schematic
presentation of the preparation of floating microparticles
based on low-density foam powder, using (a) The solvent evaporation method or
(b) The soaking method.
B)
IONOTROPIC GELATION METHOD
Figure 4: Ionotropic
gelation method
C) EMULSION SOLVENT DIFFUSION METHOD