Barrier layers in multilayered tablets
The challenging aspect of controlled drug delivery has been
the design of matrix systems that provide zero-order kinetics for total drug
release with no time lag or burst effect over a prolonged period to optimise
therapy. The answer seems to be a triple layer matrix system, with barrier layers
between core and dissolution medium
In recent years, the study of controlled release of drugs and other bioactive
agents from polymeric devices has attracted many researchers around the world.
Controlled drug delivery applications include both sustained delivery over hours/days/
weeks/months/years and targeted (e.g., to a tumour, diseased blood vessel, etc.)
delivery on a one-time or controlled basis. Oral modified/controlled release
delivery systems offer a number of advantages including improvement in patient
compliance, greater selectivity of pharmacological activity, therapeutic efficiency
and safety, decreased side effects, and reduced dosing frequency. Over years
of research, different systems, ranging from coated tablets and gels to biodegradable
microspheres and osmotic systems, have been explored experimentally and computationally
to get pre-designed release profiles.
The most common controlled delivery system has been the matrix system containing
uniformly dissolved or dispersed drug, such as tablets and granules, because
of its effectiveness as well as low cost and ease of manufacturing. Hydrophilic
polymers are becoming very popular in formulating oral controlled release tablets.
Various synthetic polymers (hydroxypropyl methyl cellulose, sodium carboxymethyl
cellulose, poly methyl methacrylates, etc) and natural materials (xanthan gum,
guar gum, chitosan, etc.) have been tried by various researchers. It has been
shown that in case of hydrophilic matrices, swelling as well as erosion of the
polymer occurs simultaneously and both of them contribute to the overall drug
release rate. Development of oral controlled release tablets for highly water-soluble
drugs with constant release rate has always been a challenge to the pharmaceutical
Most highly water-soluble drugs, if not formulated properly, may readily release
the drug at a faster rate and are likely to produce toxic concentrations, on
oral administration. Hence, it is a demanding task to formulate a suitable tablet
dosage form for controlled delivery of highly water-soluble drugs. Oral solid
dosage forms based on three-layer matrix principle have been well explored as
an approach to achieve controlled delivery of such candidate, and are now commercially
available. Recently, a new method based on the application of an inert impermeable
press-coating on both faces of matrix tablet was proposed. Barrier layers delay
the interaction between core and dissolution medium. This article gives an overview
on how triple-layer matrix system overcomes disadvantages of non-linearity associated
with conventional diffusion controlled matrix devices by providing additional
release surface with time to compensate for the decreasing release rate.
Reason for Multilayered Tablets:
- Physical/Chemical Separation: It is possible
to avoid the incompatibility in between active-active; excipient-excipient
and active-excipients by mean of physical separation. Well known example of
such an interaction is a Millard reactions occuring during tablet compression.
- Multiple release profile: Such drug delivery
systems are able to provide multiple release kinetics of same/different drugs
of same or different physicochemical properties by application of multiple
layers. Each monolith was formulated in order to parcel out the delivery of
drug dose by means of different release control mechanisms.
- Immediate Release (Disintegrating monolith):
Disintegrating monolith deliver the initial quick release required to achieve
peak plasma concentration. Introduction of initial loading dose in conventional
dosage form were neglected by application of such technique.
- Delay Release (Erodible monolith): Delay
release achieved by application of erodible monolith, which deliver the second
installment of actives in the latter part of gastrointestinal tract (GIT).
- Controlled Release (Swelling monolith): Swelling
monolith perform by both swelling as well as eroding mechanism in which drug
were continuously released throughout the GIT.
- To produce repeat action: Multilayered tablets
readily lend themselves to repeat-action products, wherein one layer of the
layered tablet or the outer tablet of the compression coated tablet provides
the initial dose, rapidly disintegrating in the stomach. The inner tablet
is formulated with components that are insoluble in gastric media but release
in the intestinal environment
- Better Management of Release Profile: Layering
in the tablet is one of the realistic means of gaining a better management
on release profile. It is a viable alternative to conventional matrix tablets
to circumvent the initial burst release and to achieve zero-order release
Problems encountered with conventional matrix tablet
Some of the serious problems faced by single unit matrix formulation with highly
soluble drugs are as below.
- Burst effect: In case of many controlled
release formulations, upon placement in the release medium, there is an immediate
release of an initial large bolus of drug is released before the release rate
reaches a stable profile. This phenomenon is typically referred to as 'burst
- First order release kinetics
- Increase in metabolic rate: This leads to higher
initial drug delivery and also reduces the effective lifetime of the device.
- Increase in dosing frequency etc.
Multilayered Matrix tablets - a way to overcome the
disadvantages of conventional matrix tablets:
Three - layered tablets for controlled release usually consist of a drug core
layer sandwiched by external layers, which may contain different amounts of
drug to form a concentration gradient matrix or just act as a barrier layer.
In general, drug release modulation from the three-layered matrix system can
be accomplished via the following geometric modifications:
(a) Formation of drug concentration gradient and differential
erosion of the matrix layers
(b) Restriction of release surface of swellable matrix by barrier layers
(c) The swelling and differential erosion of external layers to maintain constant
surface area and constant release
(d) Differential layer dissolution for pulsatile or rapid-slow release purposes
Some of the advantages of three-layered matrix system over matrix delivery systems
and devices, used in constant rate delivery, include the maximum flexibility
in drug release patterns, ease of manufacturing, drug release, improved patient
convenience, increase in safety margin of high potency drug, maximum utilisation
and reduction in health care cost etc.
The manufacturing of multilayered tablets involves the following steps,
a. Dosing of the bottom layer
b. Transfer of the prepared core
c. Insertion in to die
d. Dosing of the top layer
e. Final compression and
The manufacturing of the matrix core is performed in a separate step and is
usually performed on a regular rotatory press. Since the cover layer plays a
critical role in the drug release mechanism, its weight, thickness, and compaction
need to be tightly controlled during final compression. This process requires
specialised equipment that involves transfer punches and exact positioning of
core in die.
It was possible to design a novel triple layered tablet dosage form based on
multi-layered tablet technology and the desired surface area exposed per unit
time. Successful formulation of various highly soluble drugs laminated with
hydrophilic matrices was also possible and it was feasible to achieve a variety
of drug release profiles, such as zero order, first order and multi-modal, by
slightly varying the break up of drug content between the layers and the polymer
concentration and composition in core tablet.
(The author is a research scholar from K M Kundani College
of Pharmacy, Mumbai. He can be contacted at firstname.lastname@example.org)