Sustained release

INTRODUCTION
Sustained released
Before initiating a discussion of sustained release dosage forms, it is necessary to
provide a short explanation of terminology used because there is considerable
confusion in this area. The general consensus is that controlled release denotes
systems, which can provide some control, whether this is of a temporal or spatial
nature, or both, of drug release in the body. In other words, the systems attempts to
control drug concentration in the target tissue or cells. Thus, prolonged release or
sustained release systems, which only prolong therapeutic blood or tissue levels of
the drug for an extended period of time, cannot be considered as controlled release
systems by this definition. They are distinguished from rate-controlled drug
delivery systems, which are able to specify the release rate and duration in vivo
precisely, on the basis of simple in vitro tests. Drug targeting, on the other hand,
can be considered as a form of controlled release in that it exercises spatial control
of drug release within the body.
Sustained release describes the release of drug substance from a dosage form or
delivery system over an extended period of time. 1 The basic goal of this system is
to achieve a steady state blood level that is therapeutically effective and non-toxic
for an extended period of time. The design of proper dosage regimens is an
important element in accomplishing this goal. Sustained release, sustained action,
controlled release, extended action, timed release, depot and repository dosage
forms are terms used to identify drug therapy systems that are designed to achieve
a prolonged therapeutic effect by continuously releasing medication over an
extended period of time after administration of single dose. In the case of
injectable dosage forms, this period is measured in hours and critically depends on
the residence time of the dosage form in the gastrointestinal tract. The term
controlled release has become associated with those systems from which
therapeutic agents may be automatically delivered at predetermined rates over a
long period of time. Products of this type have been formulated for oral, injectable
and topical use and inserts for placement in body cavities.2 Controlled release
systems also denotes systems which can provide some control whether this be of a
temporal or spatial nature or both, of drug release in the body. The system attempts
to control drug concentrations in the target tissues or cells.
Prolonged or sustained release systems only prolong therapeutic blood or tissue
levels of the drug for an extended period of time.

Sustained release

Sustained release is a type of dosage form which is designed to release a drug at a

predetermined rate in order to maintain a constant drug concentration for a specific
period of time with minimum side effects. Sustained release's definition is more
akin to a "controlled release" rather than "sustained". It denotes a drug preparation
in a capsule containing numerous tiny pellets with different coatings that release
their contents steadily over a long period. Sustained Release and Prolonged
Release are same and can be used interchangeably

A drug delivery system (DDS) is defined as a formulation or a device that enables

the introduction of a therapeutic substance in the body and improves its efficacy
and safety by controlling the rate, time, and place of release of drugs in the body.
This process includes the administration of the therapeutic product, the release of
the active ingredients by the product, and the subsequent transport of the active
ingredients across the biological membranes to the site of action. The term
therapeutic substance also applies to an agent such as gene therapy that will induce
in vivo production of the active therapeutic agent. Drug delivery system is an
interface between the patient and the drug. It may be a formulation of the drug to
administer it for a therapeutic purpose or a device used to deliver the drug. This
distinction between the drug and the device is important, as it is the criterion for
regulatory control of the delivery system by the drug or medicine control agency. If
a device is introduced into the human body for purposes other than drug
administration, such as therapeutic effect by a physical modality or a drug may be
incorporated into the device for preventing complications resulting from the
device, it is regulated strictly as a device. There is a wide spectrum between drugs

Sustained release

and devices, and the allocation to one or the other category is decided on a case by
case basis. Sustained release (SR) preparations are not new but several new
modifications are being introduced. They are also referred to as long acting or
delayed release when compared to rapid or conventional release
preparations. The term sometimes overlaps with controlled release, which
implies more sophisticated control of release and not just confined to the time
dimension.Now a days conventional dosage forms of drugs are rapidly being
replaced by the new and the novel drug delivery systems. Amongst, these the
controlled release/sustained release dosage forms have become extremely popular
in modern therapeutics. Matrix system is the release system which prolongs and
controls the release of the drug, which is dissolved or dispersed. A matrix is
defined as a well-mixed composite of one or more drugs with gelling agent i.e.
hydrophilic polymers. Introduction of matrix tablet as sustained release (SR) has
given a new breakthrough for novel drug delivery system in the field of
Pharmaceutical technology [1]. Sustained release constitutes any dosage form that
provides medication over an extended time or denotes that the system is able to
provide some actual therapeutic control whether this is of a temporal nature, spatial
nature or both. Sustained release system generally do not attain zero order type
release and usually try to mimic zero order release by providing drug in a slow first
order. Repeat action tablet are an alternative method of sustained release in which
multiple doses of drug are an alternative method of Sustained release, in which,
multiple doses are contained within a dosage form and each dose is released at a
periodic interval. Oral drug delivery has been known for decades as the most
widely utilized route of administration among all the routes that has been explored
for the systemic delivery of drugs via various pharmaceutical products of different
dosage form. Nowadays most of the pharmaceutical scientists are involved in
developing an ideal DDS. This ideal system should have advantage of single dose
for whole duration of the treatment and it should deliver the drug directly at
specific site. Scientists have succeeded to develop a system that can be as near to
an ideal system and it encourages the scientists to develop controlled release
system. The design of oral sustain drug delivery system (DDS) should be primarily
aimed to achieve the more predictability and reproducibility to control the drug
release, drug concentration in the target tissue and optimization of the therapeutic
effect of a drug by controlling its release in the body with lower and less frequent
dose. Conventional drug therapy typically involves the periodic dosing of a
therapeutic agent that has been formulated in a manner to ensure its stability,
activity and bioavailability. For most of the drugs, conventional methods of
formulation are quite effective. However some drugs are unstable and toxic and
have a narrow therapeutic range, exhibit extreme solubility problems, require
localization to a particular site in the body or require strict compliance or long-term

Sustained release

use. In such cases a method of continuous administration of drug is desirable to

maintain fixed plasma drug levels. The goal in designing sustained or sustained
delivery systems is to reduce the frequency of the dosing or to increase
effectiveness of the drug by localization at the site of action, reducing the dose
required or providing uniform drug delivery. So, sustained release dosage form is a
dosage form that release one or more drugs continuously in a predetermined
pattern for a fixed period of time, either systemically or to a specified target organ.
Sustained release dosage forms provide a better control of plasma drug levels, less
dosage frequency, less side effect, increased efficacy and constant delivery existing
international patents, discovery of new polymeric materials suitable for prolonging
the drug release, and the improvement in therapeutic efficiency and safety achieved
by these delivery systems. Now-a-days the technology of sustained
Release is also being applied to veterinary products. These systems also provide a
slow release of drug over an extended period of time and also can provide some
control, whether this be of a temporal or spatial nature, or both, of drug release in
the body, or in other words, the system is successful at maintaining constant drug
levels in the target tissue or cells
.
Diclofenac sodium is an odourless, yellowish-white, crystalline powder sparingly
soluble in
water. In addition to diclofenac sodium, DICLOFENAC-GA tablets contain
lactose, calcium hydrogen phosphate, cellulose- microcrystalline, starch-maize,
sodium starch glycollate,
magnesium stearate, silica-colloidal anhydrous, methacrylic acid copolymer,
triethyl citrate talc-purified, titanium dioxide and iron oxide yellow
Nonsteroidal anti-inflammatory drugs used to relieve the inflammation, swelling,
stiffness, and joint pain associated with rheumatoid arthritis, osteoarthritis
Diclofenac is official in the Martindale Extra Pharmacopoeia. It is a nonsteroidal
anti inflammatory agent used for a variety of painful and inflammatory conditions.
It has a short biological half life 1-2 hours and is administered in a dose of 150mg
2-3 times a day. Therefore this drug is an ideal candidate for developing sustained
release dosage forms which could result in prolonged clinical efficacy reduced
frequency of administration and less side effects. The simplest and least expensive
way to control the release of drug is to disperse it within an inert polymer matrix.
Because of their simplicity and cost effectiveness hydrophilic gel matrix tablets are
widely used for sustained release dosage forms. These materials form a gel like
structure around the tablet core which sustains the release process. Hydrophilic
polymers are most widely used for preparation of matrix tablets. But use of
Hydrophilic polymers alone for controlling the release of water soluble drug is

Sustained release

probably restricted due to rapid diffusion of water soluble drug Hydrophobic

waxes have been extensively investigated for sustained release of drug. This
provides good stability at varying pH and effective retarding of water soluble drug.
In forming a wax matrix system different processing methods like dry blending,
wet granulation, melt granulation and extrusion, spheronization are used. In the
present study water soluble drug is 1st incorporated in waxy material by melt
granulation technique and this matrix is subsequently granulated with hydrophilic
polymers. In this study steric acid is taken as hydrophobic wax and different
hydrophilic polymers as HPMCK4M, Sodium CMC, and Sodium Alginate are
taken in different ratios.
Oral route is very admired and commodious route of a drug administration. Oral
route of administration has been used for both conventional and novel drug delivery system. In the modern era, sustained release dosage form is suppressing the use
of conventional dosage form.1 the sustained release tablet provides uniform release
of drug over a long period of time. Controlled release dosage form covers a wide
range of prolonged action formulation which provides continuous release of their
active ingredient at a predetermined rate and time.2 Sustained or controlled drug
delivery system is to reduce the frequency of dosing or to increase the
effectiveness of drug by localization at the site of action, reducing dose required,
providing continuous drug delivery, reduce incidence of adverse effect and
maintain drug concentration in system.1,3 Matrix tablets serve as an important tool
for oral extended- release dosage forms. Hence, various problems like patient
compliance, drug targeting, local side effects, frequent administration and
fluctuations in blood concentration levels, associated with their counterparts,
therefore the conventional dosage forms restricted. A matrix tablet is the oral solid
dosage form in which the drug or active ingredient is homogeneously dispersed
throughout the hydrophilic or hydrophobic matrices which serve as release rate
retardants.1,4 Polymers are high molecular weight compound originate from
natural and synthetic source. Hydrophilic polymer (HPMC K4M) basically the
cellulose derivative use of matrices, which satisfy the key criteria of release pattern
by swelling property. HPMC is a partly o-methylated and o-(2-hydroxypropylated)
cellulose with a molecular weight 10,000-1, 5000,000. Hydrophobic polymer (acacia gum) reduced the rate and extent of drug release due to reduced porosity of
matrix. Acacia is a complex loose aggregate of sugars and hemiacetal. It is an
acidic polysaccharide containing D-galactose, L-arabinose, L-rhamanose , Dglucuronic acid with a molecular weight of approximately 240,000-500,000.5,6
Both HPMC K4M and acacia gums are cellulose polymer based matrix which
forms hydrogel due to simultaneous migration to the matrix.3

Sustained release

Diclofenac sodium is 2-[2,6dichlorophenyl-amino] phenyl acetate and soluble in

water. It is a Non- Steroidal Anti-Inflammatory Drug (NSAIDs) with analgesic
activity. It inhibits PG synthesis and is somewhat COX-2 selective. It is well
absorbed orally, 99% protein bound, metabolized and excreted both in urine and
bile.
There are various methods used in tablet manufacturing i.e. dry granulation, wet
granulation and direct compression. So, we have used the direct compression
method after mixing the all the ingredients which are required.
Direct compression is a popular choice because it provides the shortest, most
effective and least complex way to produce tablets. The manufacturer can blend an
API with the excipient and the lubricant, followed by compression, which makes
the product easy to process. No additional processing steps are required.
Moisture or heat sensitive ingredients, which would be contraindicated in wet
granulation, can also be used in this type of process. However, it does require a
very critical selection of excipients in comparison to granulation processes because
the raw materials must demonstrate good flowability and compressibility for
successful operation.

Sustained release

Both high and low doses of API present a challenge in this respect. Most APIs tend
to have poor compressibility, which affects the quality of tablets if the formulation
calls for a large proportion of API. At the same time, there can also be problems
when low amounts of actives need to be incorporated into tablets because it is
difficult to accurately blend a small amount of active in a large amount of excipient
to achieve the desired uniformity and homogeneity.
For instance, segregation of the different components can occur. This means there
is not a uniform distribution of tablet ingredients being fed to the press, and thus
batch to batch consistency of the manufactured tablet cannot be assured.
One of the principal risk factors for segregation is the wide particle size
distribution in direct compression formulations, in which active ingredients tend to
be at the fine end of the range. Where there is a wide range of particle sizes, there
is an increased likelihood of sifting, where the smaller particles 'slip through' the
bigger ones.
Other bulk powder properties are also important for successful tabletting, such as
good flow ability, and all of these factors combine to place a high requirement on
the excipients used for direct compression.

Sustained release