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World Journal of Pharmaceutical Research

Thirupathaiah et al. World Journal of Pharmaceutical Research


SJIF Impact Factor 6.805

Volume 5, Issue 7, 355-364. Review Article ISSN 2277– 7105

TRILAYER SUSTAINED RELEASE DRUGS OF ANTILIPIDEMIC


DRUGS BY GEOMATRIX TECHNOLOGY – REVIEW.

Atthapu Thirupathaiah* and Rachamallas Shyam Sunder

UCTOU, OU, Hyderabad. Telangana State, 5000007 India.

Article Received on ABSTRACT


23 April 2016,
Oral ingestion has long been the most convenient and commonly
Revised on 14 May 2016,
Accepted on 05 June 2016 employed route of drug delivery due to its ease of administration and
DOI: 10.20959/wjpr20167-6462 flexibility in the design of the dosage form. Trilayer tablets are
prepared with one layer of drug for immediate release while second
*Corresponding Author and third layers designed to release drug, later, either as second dose or
Atthapu Thirupathaiah in an extended release manner. A new delivery device, in the form of a
UCTOU, OU, Hyderabad.
multi-layer tablet, has recently been proposed for constant drug
Telangana State, 5000007
India.
release: Geomatrix® Technology. It consists of a hydrophilic matrix
core, containing the active ingredient and one or two impermeable or
semi-permeable polymeric coatings (films or compressed barriers) applied on one or both
bases of the core.

INTRODUCTION
Oral ingestion has long been the most convenient and commonly employed route of drug
delivery due to its ease of administration and flexibility in the design of the dosage form.[1]
Multilayer tablets are novel drug delivery systems where combination of two or more drugs
in a single unit having different release profiles which improves patient compliance, prolongs
the drug(s) action. Trilayer tablets are prepared with one layer of drug for immediate release
while second and third layers designed to release drug, later, either as second dose or in an
extended release manner.[2]

Sustained release systems include any drug delivery system that achieves slow release of
drug over an extended period of time. If the system is successful in maintaining constant drug
levels in the blood or target tissue, it is considered as a controlled-release system. The oral
route of administration for sustained release systems has received greater attention because of
more flexibility in dosage form design.

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Thirupathaiah et al. World Journal of Pharmaceutical Research

Drug Release Mechanism from SR MATRIX


Zero Order Kinetics
A zero order release would be predicted by the following equation,
Qt - Q0 = K0t
Where, Qt = Amount of drug release dissolved in time„t‟.
Qo = Initial amount of drug concentration in solution.

K0t = Zero order rate constant. When the data was plotted as cumulative % drug release
verses time, if the plot is linear then data obeys zero order kinetics with slope equal to Ko.
This model represents an ideal release profile in order to achieve the prolonged
pharmacological action.[3]

A new delivery device, in the form of a multi-layer tablet, has recently been proposed for
constant drug release: Geomatrix® Technology. It consists of a hydrophilic matrix core,
containing the active ingredient, and one or two impermeable or semi-permeable polymeric
coatings (films or compressed barriers) applied on one or both bases of the core (Fig. 1).

Fig. 1: Geomatrix Technology: two- and three-layer systems

The presence of the coatings modifies the hydration/swelling rate of the core and reduces the
surface area available for drug release. These partial coatings provide a modulation of the
drug dissolution profile: they reduce the release rate from the device and shift the typical
time-dependent release rate towards constant drug release.

The film coatings act as an inert and impermeable obstacle to water penetration and to drug
diffusion through the underlying protected surfaces, but, during dissolution, the shape and
extension of the film cannot change while the core swells. For this reason the core exposes in
time an increasing extension of its surface to the interaction with the dissolution medium and,

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Thirupathaiah et al. World Journal of Pharmaceutical Research

as a consequence, the protection effect of the film is progressively minimized during the
release process.

These compressed barriers prove to be much more effective and versatile compared to the
films in the modulation of the release profile and, above all, they are feasible from an
industrial standpoint.

A number of barrier compositions were formulated and tested to reach the most suitable
control of the dissolution process. In particular a barrier made up of high viscosity
hydroxypropylmethylcellulose (HPMC), which is characterized by very slow hydration and
gelling rates, provides an excellent protection of the coated surfaces of the active core for
extended times. This type of barrier, being quite impermeable to drug diffusion for long
periods of time, is particularly useful to control the release of soluble drugs for once a day
administration. On the other hand, if the device contains drugs of low solubility, the release
rates obtained are generally too slow. In this case, to maintain the linearization of the
dissolution profile, while increasing the release rate, a different approach is proposed: a new
barrier is designed whose protective effect towards hydration, swelling, erosion (and
consequently towards the release process) is time-dependent, being at the maximum at the
beginning and progressively reduced during the dissolution process (Fig. 2).

Fig. 2: Swelling behaviour of the Geomatrix three-layer systems with the different types
of barrier coatings: erodible or gellable.[4]

Such a time-dependent barrier is obtained using HPMC of low viscosity. The behaviour and
efficiency of this type of coating were tested on active cores coated by compression on the
whole surface (press-coated devices): during the dissolution test, the shell is progressively

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Thirupathaiah et al. World Journal of Pharmaceutical Research

eroded and removed from the system in a well-defined period of time and, only when the
active core is cleared of its coating, does the drug release start.

Fig 3 shows the dissolution profiles of core tablets and two types of press coated tablets[4,5]
Geomatrix technology or multilayered matrix tablet formulation, having one to three (multi)
layer matrix tablets is a drug delivery system, which consists of a matrix core containing the
active pharmaceutical ingredient and one or more barriers (modulating layers) incorporated
during process of tablet compression.[6]

Objective of preparing multilayer tablets


1. To treat critical disease condition when single active unable to produce complete
therapeutic action and to maintain over a period 12 h or more. E.g. telmisartan/amlodipine
tablet.

2. To use combination having proven advantages over single compounds administered


separately for therapeutic effect.

3. To combine different drugs for synergistic therapeutic effect or different drugs in order to
achieve a specific release profile. E.g. efavirenz, emtricitabine in multilayer tablet for the
treatment anti HIV-1 infection.

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Thirupathaiah et al. World Journal of Pharmaceutical Research

4. To overcome the limitations in case of a single drug which is unable to treat or avoid
adverse drug effect, if any.

5. To establish a brand identity, as they are clearly different from other products from generic
competitors and also from patient identity over routine white pills and when patient is unable
to take frequent dosing of same drug.

6. To get dual release profile so as to reduce tablets intake and thereby increasing patient
compliance.

7. To combine compatible or incompatible drugs with different release characteristic in same


dosage form and enhancing the stability of dosage form as compared to its conventional
monolith counterpart.[7]
The Geomatrix technology is applied to achieve customized levels of controlled release of
specific drugs and can achieve simultaneous release of two different drugs and different rates
from a single tablet. The controlled release is achieved by constructing a multilayered tablet
made of two basic key components
1) Hydrophilic polymers such as hydroxypropyl methycellulose (HPMC)
2) Surface controlling barrier layers.

Active loaded core surface that is available for drug release when exposed to the fluid is
controlled by barrier layers. The combination of layers, each with different rates of swelling,
gelling and erosion, is responsible for the rate of drug release within the body. When first
swallowed, for example, the drug concentration is high but the surface area low. As time
progresses the core swells and the surface area increases to compensate for the decrease in
drug concentration. One of the major benefits of the Geomatrix technology is its ability to be
easily incorporated into the production line. The Geomatrix tablets can be manufactured by
readily available equipment that can be integrated into widely-used pharmaceutical processes,
thus giving firms more control over their own production activities.

Advantages of the Geomatrix technology are


 Reproducibility
 Efficacy
 Versatility of release control mechanisms
 Controlled release of poorly soluble drugs
 Timed release of drug

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Thirupathaiah et al. World Journal of Pharmaceutical Research

 Bi-phasic release of drugs


 Release of 2 or more drugs at different rates
 Pulsed release of drugs
 Safety of use.[8]

Parameters to be considered during Multilayer tableting

Dwell time: It is the contact between punch head and compression roller. If shorter the first
layer-dwell time, which results into pours, aeration, capping and hardness problems. It may
be removed the mistakes by reducing the turret-rotation speed or by extending the dwell time.

Cohesiveness: When the first layer is compressed at a very high compression force, bonding
between layers is severely controlled. Various bilayer formulations necessitate a first layer
compression force NMT 3 Kpor 30 N to maintain the ability of first layer to bond with the
second layer. Thus at elevated manufacturing speed, the jeopardy of separation and capping
increases which can be minimised by adjusting adequate dwell time at all compression stages.

Risk of separation and capping: It is necessary to avoid risk of separation and capping, by
forming correct bonding which can be attained by the first layer formation at low
compression force. Therefore this first layer can still interact with the second layer during
final compression of the tablet.

Cross-contamination: Multilayer tablet machines are equipped with suction nozzles or dust
extractor to remove fine powder or granules to eliminate cross-contamination between the
two layers and getting a clear visual separation between layers. It is very important to remove
any powder residue from the die plate and for this purpose dedicated scraper plate are located
before and after each die fill, to remove residual powder dust to the outside of the die table,
where the high efficiency suction nozzles are located.

Final compression force: This force is applied on the final bilayer tablet is always more than
the compression force on first layer, which results in suitable bonding of both the layers.

Weight variation: Weight variation occurs some time due to non-uniform flow of granules,
incomplete die filling and lower punch jamming due to excessive fines in final blend and thus
these parameters should be controlled carefully during tabletting.

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Thirupathaiah et al. World Journal of Pharmaceutical Research

Weight adjustment: First layer pressure is useful for weight adjustment of second layer.
Many formulators use such technique to achieve desired weight instead of using weight
adjustment knob that totally depends on handling experience of such double rotary press.

Hardness and Thickness: This parameters need to be tightly controlled during final
compression because it directly affect the release of active. Many times due to high hardness
disintegrating matrix may take time more than limits.[9]

ADVANTAGES
Better execution of release profile Layering on the tablet revealed better execution on release
profile and it is one of the most important possible alternatives to conventional matrix tablets
to avoid the initial burst release and to achieve zero-order release profile, which maintain
availability of drug over 12 h or more. Eg. Venlafaxine hydrochloride.

Decrease burst effect and fast initial release rate Upon placement of controlled release
formulation in release medium or in dissolution medium, there is an immediate release of an
initial large bolus of drug, before the release rate reaches a stable profile (stable matrix
formation). This phenomenon is typically referred to as 'burst release' which is controlled
using multilayer tableting.eg. Terazosin HCl.

Multiple release profiles: Two or more layers in tablets are able to provide multiple release
kinetics of same or different drugs of same or different physicochemical properties and it is
possible to formulate each monolith in order to parcel out the delivery of drug dose by means
of different release control mechanisms. Eg. Naproxen, loratadine and pseudoephedrine.

Synergistic effects: It is well known that presence of one drug enhances the effects of the
second and formulation of two or more drugs together in single tablets offer therapeutic effect
of these drugs is greater than the sum of the individual effects.

Reduction in dosing frequency It is possible to formulate one layer in the form of immediate
release disintegrating monolith that deliver the initial quick release required to achieve peak
plasma concentration and then sustaining the same drug over the period of time more than 12
h so the multiple intake dosing frequency minimize and thus get programmable drug delivery
system of same or different active in single dose and thus reduction in dosing frequency.

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Delayed Release Application of erodible monolith for immediate and delayed release pattern
is possible, which deliver the second instalment of drugs in the latter part of GIT. E.g.
naproxen and esomeprazole magnesium.

Controlled Release Swelling monolith carry out by both swelling as well as eroding
mechanism in which drug was continuously released throughout the GIT. E.g.
Trimetazidinedihydrochloride.

Patient compliance: Improved patient compliance by reducing tablet intake, "Layers" in


tablets represented by two or more different colours and produces a product that looked more
attractive than a standard white "pill".

DISADVANTAGES
Problems during In-process Quality Control (IPQC): In-process problems during bilayer
compression such as layer separation (delamination) occurs; sometimes not immediately but
may be after compaction i.e. during storage, packaging, shipping. Problem such as
insufficient hardness, inaccurate individual layer weight control, cross-contamination
between the layers, insufficient binding between layers, reduction in practical yield of final
compressed tablets, clear visual separation between the two layers are commonly observed.

Analytical Development and Pharmacopoeial Monograph It has been observed that very few
FDCs monographs are available in various pharmacopoeias like USP, JP, IP, BP etc.
Analytical developments of many FDCs are not included in pharmacopoeias. Preparations of
finished product specification take long time for development of dissolution testing, assay,
content uniformity and characterization of impurities. Moreover, issue related to development
of cleaning validation, detection of residue after cleaning validation, determination of LOD,
selection of primary packaging material for different types of physicochemical properties of
individual active pharmaceutical ingredients in finished products are to be addressed.

Regulatory: It is true that development of FDCs should always be based on believable


therapeutic and medical justification which is clinically relevant. Hence various
pharmaceutical companies are demanding that individual compounds of same formulation
available in market are safe and effective since long time and therefore FDCs of same are
also safe but DCGI had restriction for development of FDCs. Unfortunately, many FDCs
have been introduced in Indian market are usually irrational and therefore, many irrational

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combinations are banned by DCGI and guidelines were issued for getting marketing approval
of FDCs. These guidelines concern to manufacture/ import and marketing approvals.

Machine setup: Set up of bilayer or trilayer tablets is time consuming, take long time to
initial setup, speed, requirement of skilled person and many times problem arise during
tableting as compared to single layer conventional tablet press in machine setup, cost and
production output.[7]

REFERENCES
1. Potturi PK, Sudhakar Y. rmulation and In vitro/In vivo evaluation of controlled release
Entacapone trilayer matrix tablets by geomatrix. International Journal of Drug Delivery.
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2. Natarajan R, Ramcy TR, Sharadhamani G, Anusha K, Thangadurai SA.
FORMULATION AND EVALUATION OF TRILAYER AND BILAYER TABLETS
OF NEVIRAPINE, ZIDOVUDINE AND LAMIVUDINE. South Pacific Journal of
Pharma and Bioscience 2014; 2(2): 123-125.
3. Sarika, Pundir; Ashutosh, Badola and Deepak, Sharma. “Sustained Release Matrix
Technology and Recent Advance in Matrix Drug Delivery System: A Review”,
International Journal of Drug Research and Technology 2013; 3(1): 12-20.
4. Conte U, Maggi L. Geomatrix® system• for controlled release of drugs. Department of
Pharmaceutical Chemistry. University of Pavia. Italy.< http://www. unipr.
it/arpa/dipfarm/conf/abstracts/conte. html>(accessed 20 June 2000).
5. Chaerunisaa AY. Release adjustment of drug combinations with different drug
solubility (Doctoral dissertation, Freie Universität Berlin).
6. Bakshi KS et al., INVESTIGATION ON THE IMPACT OF CORE AND BARRIER
LAYER COMPOSITION ON THE DRUG RELEASE FROM A TRIPLE LAYER
TABLET. International Journal of Pharmaceutical Sciences and Research. 2012 Jul 1;
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7. Shende P, Shrawne C, Gaud RS. Multi-layer Tablet: Current scenario and recent
advances. International Journal of Drug Delivery. 2012 Oct 1; 4(4): 418.
8. Ramteke KH, Dhole SN, Chavanke MS. Recent technologies for pulsatile drug delivery
system. International Journal of Pharmaceutical and Chemical Sciences 2013; 2(3): 1369-
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9. Gavate NT, Gondkar SB, Saudagar RB. MULTILAYER TABLET: A NEW TREND IN
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