L-OROS®
technology[6]
The L-Oros®
system was designed to provide continuous delivery of liquid drug formulations
and improve bioavailability of the drugs. L-Oros
system consists of two types i.e., soft gelatin capsule (SoftcapTM)
and hard gelatin capsule (HardcapTM). Both have a
drug layer, barrier layer and a push layer surrounded by a semipermeable
membrane with a delivery orifice. The L-OrosHardcap
system was designed to accommodate more viscous suspensions with higher drug
loading than Softcap design.
EN
SO TROL technology [7]
Solubility enhancement of an order of
magnitude or to create optimized dosage form Shire laboratory use an integrated
approach to drug delivery focusing on identification and incorporation of the
identified enhancer into controlled release technologies.
DUREDASTM
technology [7]
DUREDAS or Dual Release Drug Absorption
System (Elan Corporation) utilizes bilayer tableting technology,
which has been specifically developed to provide two different release rates or
dual release of a drug from a single dosage form. The tablets are prepared by
two separate direct compression steps that combine an immediate release
granulate (for rapid onset of action) and a controlled release hydrophilic
matrix complex within one tablet. The controlled release matrix remains intact
and slowly absorbs fluid from the GI tract, which causes the matrix. To expand
and transforms the hydrophilic polymers into a porous, viscous gel that serves
as a barrier between the drug and the surrounding fluid. As the gel continues
to expand, fluid penetrates further into the dosage form, dissolving the drug
and allowing the resulting solution to diffuse out in a controlled manner. A
further extension of the duredas technology is the
production of controlled release combination dosage forms whereby two different
drugs are incorporated into the different layers, and the drug release of each
layer is controlled to maximize therapeutic effect of the combination. Again
both immediate release and controlled release combinations of the two drugs are
feasible.
Benefits
offered by the DUREDAS™ technology include:
v Bilayer tableting
technology.
v Tailored release rate of two drug components.
v Capability of two different control release
formulations combined.
v Capability for immediate release and
modified release components in one tablet
v Unit dose tablet presentation
DUROS
technology [7]
DUROS (Alza
Corporation) is based on implant technology, which provides an alternative for
the delivery of a wide range of therapeutic compounds, including peptides,
proteins, and other bioactive macromolecules. These implants are miniature
titanium cylinders designed to provide continuous osmotically
driven delivery of drugs within the body for up to one year. Following
implantation, DUROS implants enable continuous, precise delivery of the
therapeutic compound at rates as low as 1% of a drop of water per day. The
cylinder is manufactured from titanium because of the material’s tolerability
to human tissue and its long use in medical devices such as implantable
defibrillators and joint replacements. The cylinder protects therapeutic agents
from degradation in the body and enables a drug to remain stable for extended
periods of time. Recently, Viadur (leuprolide acetate implant), which is based upon this
technology, has been approved for once yearly palliative treatment of advanced
prostate cancer
Fig 9: DUROS technology
PRODAS
technology [7]
PRODAS or Programmable Oral Drug Absorption
System (Elan Corporation) is a multi-particulate drug
delivery technology that is based on the encapsulation of controlledrelease
minitablets in the size range of 1.5 to 4 mm in
diameter. This technology represents a combination of multi-particulate and
hydrophilic matrix tablet technologies and thus provides the benefits of both
these drug delivery systems in one dosage form. Mini-tablets with different
release rates can be combined and incorporated into a single dosage form to
provide the desired release rates. These combinations may include immediate
release, delayed release, and/or controlled release minitablets.
In addition to controlled absorption over a specified period, PRODAS technology
also enables targeted delivery of drug to specified sites of absorption
throughout the GI tract. Combination products also are possible by using
mini-tablets formulated with different active ingredients.
GEMINEX
technology [8]
Geminex is a dual drug delivery technology that
can deliver one or more drugs at different times. The Geminex
technology controls the release rate of the two drugs to maximize their
individual therapeutic effect and minimize side effects. The benefit of geminex to the pharmaceutical industry, and ultimately to
patients, is that two different actives or the same active can be delivered at
differing rates in a single tablet. Penwest is
actively applying its geminex technology to the
following therapeutic areas: cardiovascular disorders, diabetes, cancer and
disorders of the central nervous system
Various
Approaches Used in the Bilayer Tablet: [9]
Floating
Drug Delivery System
These are designed to have a low density
and thus float on gastric contents after Administration until the system either
disintegrates or the device absorbs fluid to the point Where its density is
such that it loses buoyancy and can pass more easily from the stomach with a
wave of motility responsible for gastric emptying. The bilayer
tablet is designed in such a manner that one layer gives the immediate dosing
of the drug which gives faster onset of action while other layer is designed as
a floating layer which floats in the stomach (GI-fluid).
Disadvantages:
It may not have the controlled loss of
density alternatively required for it to eventually exit from the stomach.
Floating tablets are not applicable to higher dose levels of highly water
soluble drugs where large amounts of polymer are needed to retard drug release,
as in case of water soluble drugs. The performance of floating formulation may
also be posture dependant. A patient sitting upright may ensure prolonged
gastric residence of a buoyant dosage form, whereas a supine patient might
allow ready presentation of the floating dosage form to the pylorus and thus
allow rapid exit of the dosage form from the stomach. Hence, floating dosage
forms might be expected to only have limited applications.
Polymeric
Bioadhesive System
These are designed to imbide
fluid following administration such that the outer layer becomes a viscous,
tacky material that adheres to the gastric mucosa/mucus layer. This should
encourage gastric retention until the adhesive forces are weakened. These are
prepared as one layer with immediate dosing and other layer with bio-adhesive
property.
Disadvantages: The success seen in animal models with
such system has not been translated to human subjects due to differences in
mucous amounts, consistency between animals and humans. The system adheres to
mucous not mucosa. The mucous layer in humans would appear to slough off
readily, carrying any dosage form with it. Therefore bioadhesive
dosage form would not appear to offer a solution for extended delivery of drug
over a period of more than a few hours.
c)
Swelling System
These are designed to be sufficiently small
on administration so as not to make ingestion of the dosage form difficult
(e.g., less than approximately 23 mm long and less than 11 mm wide for an oval
or capsule –shaped tablet whereas 10- 12mm in diameter for round tablets). On
ingestion they rapidly swell or disintegrate or unfold to a size that precludes
passage through the pylorus until after drug release has progressed to a
required degree. Gradual erosion of the system or its breakdown into smaller
particles enables it to leave stomach. The simple bilayer
tablet may contain an immediate release layer with the other layer as extended
release or conventional release.
EVALUATION
OF SUSTAIN RELEASE BILAYER TABLET [10]
Tablet
Thickness and Size
Thickness and diameter of tablets were
important for uniformity of tablet size. Thickness and diameter was measured
using venire calliper.
Tablet
Hardness
The resistance of tablets to shipping or
breakage under conditions of storage, transportation and handling before usage
depends on its hardness. The hardness of tablet of each formulation was
measured by Monsanto hardness tester. The hardness was measured in kg/cm2.
Friability
Friability is the measure of tablet
strength. Electrolab EF-2 friabilator
(USP) was used for testing the friability using the following procedure. Twenty
tablets were weighed accurately and placed in the tumbling apparatus that
revolves at 25 rpm dropping the tablets through a distance of six inches with
each revolution. After 4 min, the tablets were weighed and the percentage loss
in tablet weight was determined.
Percentage loss = [(Initial wt. of tablets
– Final wt. of tablets)/ Initial wt. of tablets] ×100
Uniformity
of weight
Twenty tablets were selected at random and
the average weight was calculated. Weight Variation was calculated and was
compared with I. P. standards.
CHARACTERAIZATION
OF BILAYER TABLETS [11]
Particle
size distribution
The particle size distribution was measured
using sieving method
Photo-microscope
Study
Photo-microscope image of TGG and GG was
taken (X450 magnifications) by photomicroscope
Angle
of Repose
The diameter of the powder cone was
measured and the angle of repose was calculated using the following equation.
Tan Ř=h/r
Where h and r are the
height and radius of the powder cone.
Moisture
Sorption Capacity
All disintegrates have capacity to absorb
moisture from atmosphere which affects moisture sensitive drugs. Moisture
sorption capacity was performed by taking 1 g of disintegrate uniformly
distributed in Petri-dish and kept in stability chamber at 37±1°C and 100%
relative humidity for 2 days and investigated for the amount of moisture uptake
by difference between weights.
Density
The loose bulk density (LBD) and tapped
bulk density (TBD) were determined and calculated using the following formulas.
LBD = weight of the powder/volume of the
packing
TBD = weight of the powder/tapped volume of
the packing
Compressibility
The compressibility index of the disintegrate was determined by Carr’s compressibility
index.
VARIOUS
TYPES OF BI-LAYER TABLET PRESSES [12]:
Single
sided press
Various types of bi-layer presses have been
designed over the years. The simplest design is a single sided press with both
chambers of the double feeder separated from each other. Each chamber is
gravity- or forced-fed with a different powder, thus producing the two
individual layers of the tablet. When the die passes under the feeder, it is at
first loaded with the first-layer powder followed by the second-layer powder.
Then the entire tablet is compressed in one or two steps (two = pre- and main
compression). The two layers in the die mix slightly at their interface and in
most cases bond sufficiently so that no layer-separation occurs when the tablet
is produced. This is the simplest way of producing a bilayer
tablet.
Limitations of single-sided press.
Various types of bi-layer presses have been
designed over the years. The simplest design is a single-sided press with both
chambers of the double feeder separated from each other. Each chamber is
gravity- or forced-fed with a different powder, thus producing the two
individual layers of the tablet. When the die passes under the feeder, it is at
first loaded with the first-layer powder followed by the second-layer powder.
Then the entire tablet is compressed in one or two steps (two = pre- and main
compression). The two layers in the die mix slightly at their interface and in
most cases bond sufficiently. So the layer-separation does not occur when the
tablet is produced. This is the simplest way of producing a bilayer
tablet.
It undergoes certain limitation as follow
No weight monitoring/control of the
individual Layers.
v No distinct visual separation between the
two Layers.
v Very short first layer-dwell time due to
the small compression roller, possibly resulting in poor deaeration,capping and hardness problems. This may be corrected
by reducing the turret-rotation speed (to extend the dwell time) but with the
consequence of lower tablet output.
v Very difficult first-layer tablet sampling
and sample transport to a test unit for in-line quality control and weight
recalibration to eliminate these limitations, a double-sided tablet press is
preferred over a singlesided press. A double-sided
press offers an individual fill station, pre -compression and main compression
for each layer. In fact, the bi-layer tablet will go through 4 compression
stages before being ejected from the press
Double-sided
tablet presses:
Double-sided tablet presses have been
specifically designed and developed for the production of quality bilayer tablets and provide:
v Displacement weight monitoring/control for
accurate and independent weight control of the individual layers
v Low compression force exerted on the first layer to avoid capping and separation of the two individual
layers
v increased dwell time at pre-compression of
both first and second layer to provide sufficient hardness at maximum turret
speed
v Maximum prevention of cross-contamination
between the two layers
v A clear visual separation between the two
layers
v maximised yield
Preparation
of Bilayer Tablet [13]:
Bilayer tablets are prepared with one layer of
drug for immediate release with the second layer designed to release drug
later, either as a second dose or in an extended release form8. The bilayer tablets with two incompatible drugs can also be
prepared by compressing separate layers of each drug so as to minimize area of
contact between two layers. An additional intermediate layer of inert material
may also be included.