MAKALAH FARMASETIKA DASAR

MODIFIED RELEASE DOSAGE FORM

Oleh :

Winda (1918031017)

PROGRAM STUDI FARMASI

FAKULTAS KEDOKTERAN

UNIVERSITAS LAMPUNG

2020
 MODIFIED RELEASE DOSAGE FORM

Drug products that provide extended or sustained release (SR) first appeared as a
major new class of dosage form in the late 1940s and 1950s. Over the years, many terms
(and abbreviations), such as sustained release (SR), sustained action (SA), prolonged
action (PA), controlled release (CR), extended release (ER), timed release (TR), and
long acting (LA), have been used by manufactures to describe product types and
features. Although these terms often have been used interchangeably, individual
products bearing these descriptions may differ in design and performance and must be
examined individually to ascertain their respective features.

For the most part, these terms are used to describe orally administered dosage forms,
whereas the term rate-controlled delivery is applied to certain types of drug delivery
systems in which the rate of delivery is controlled by features of the device rather than
by physiologic or environmental conditions like gastrointestinal pH or drug transit time
through the gastrointestinal tract. In recent years, modified release has come into
general use to describe dosage forms having drug-release features based on time,
course, and/or location that are designed to accomplish therapeutic or convenience
objectives not offered by conventional or immediate-release forms. The USP recognizes
several types of modified-release systems including extended release, delayed release,
or targeted release. However, expressions such as prolonged-action, repeat-action,
controlled-release, modified-release, and sustained-release have also been used to
describe such dosage forms.

1. Extended Release

A dosage form that allows at least a twofold reduction in dosage frequency as

compared to that drug presented as an immediate-release (conventional) dosage
form. The US Food and Drug Administration (FDA) defines an extended-release
dosage form as one that allows a reduction in dosing frewuency from that
necessitated by a conventional dosage form, such as a solution or an immediate-
release dosage form. Examples of extended-release dosage forms include controlled-
release, sustained-release, and long-acting drug products. In general, the drugs best
suited for incorporation into an extended-release product have the following
characteristics :

 They exhibit neither very slow nor very fast reates of absorption an excretion.
Drugs with slow rates of absorption and excretion are usually inherently long
acting, and it id not necessary to prepare them in extended-release forms. Drugs
with very short half-lives, that is, less than 2 hours, are poor candidates for ER
because of the large wuantities of drug required for such a formulation. Also,
drugs that act by affecting enzyme systems may be longer acting than indicated
by their quantitative half-lives because of residual effects and recovery of the
diminished biosystem.
 They are uniformly absorbed from the gastrointestinal tract.
Drugs prepared in extended-release forms must have good aqueous solubility
and maintain adequate residence time in the gastrointestinal tract. Drugs
absorbed poorly or at varying and unpredictable rates are not good candidates
for extended-release products.
 They are administered in relatively small doses.
Drugs with large single doses frequently are not suitable for ER because the
tablet or capsule needed to maintain a sustained therapeutic blood level of the
drug wouls be too large for the patient to swallow easily.
 They posses a good margin of safety.
The most widely used measure of the margin of a drug’s safety is its therapeutic
index, that is, the median toxic dose devided by the median effective dose. For
very potent drugs, the therapeutic index may be narroe or vey small. The larger
the therapeutic index, the safer the drug. Drugs that are administered in very
small doses or posses very narrow therapeutic indices are poor candidates for
formulation into extended-release formulations because of technologic
limitations of precise control over release rates and the risk of dose dumping due
to a product defect. Patient misuse (e.g., chewing dosage unit) also could result
in toxic drug levels.
 They are used in the treatment of chronic rather than acute conditions.
 Drugs for acurate conditions require greater adjustment of the dosage by the
physician than that provided by extended-release products.

2. Delayed Release

Delayed-release dosage forms can be defined as systems which are formulated to

release the active ingredient at a time other than immediately after administration.
Delayed release from oral dosage forms can control where the drug is released, e.g.
when the dosage form reaches the small intestine (enteric-coated dosage forms) or
the colon (colon-specific dosage forms). Delayed-release systems can be used to
protect the drug from degradation in the low pH environment of the stomach or to
protect the stomach from irritation by the drug. In these cases drug release should be
delayed until the dosage form has reached the small intestine. Often polymers are
used to achieve this aim. The dosage form (for example, a tablet or the granules
before tableting) can be coated with a suitable polymer. The polymer dissolves as a
function of pH, so when the dosage forms travel from the low-pH environment of the
stomach to the higher-pH environment of the small intestine, the polymer coat
dissolves and the drug can be released. Once this occurs, the release is again
immediate and the resulting plasma concentration versus time curve is similar to the
one for immediaterelease dosage forms. The development of colon-specific drugs
and dosage forms may be advantageous for the treatment of local and systemic
diseases, including colorectal cancer and Crohn’s disease. Especially for peptide and
protein drugs, this form of release may also be advantageous for systemic
administration given the more favourable pH conditions in the colon compared to the
stomach and the generally lower enzymatic activity compared to the small intestine.
Picture below shows an idealised plasma concentration versus time profile of a
delayed-release oral dosage form. Tmax (but not Cmax) is strongly dependent on the
gastric emptying times which, as stated above, may be quite variable.
3. Targetted Release

Two types of targetted dosage forms are commonly described: site-spesific targeting
and receptor targeting. In site-specific targeting, drug release is at the diseased organ
or site of absorption, while in receptor targeting, drug release is at the receptor for the
drug action. Whilst controlling the rate of release of a drug from its delivery system
can control plasma drug concentration levels, once released there is often little
control over the distribution of the drug in the body. Very few drugs bind exclusively
to the desired therapeutic target and this can give rise to reduced efficacy and
increased toxicity. Drug targeting aims to control the distribution of a drug within the
body such that the majority of the dose selectively interacts with the target tissue at a
cellular or subcellular level. By doing so, it is possible to enhance the activity and
specificity of the drug and to reduce its toxicity and side-effects. Drug targeting can
be achieved by designing systems that passively target sites by exploiting the natural
conditions of the target organ or tissue to direct the drug to the target site.
Alternatively drugs and certain delivery systems can be actively targeted using
targeting groups such as antibodies to bind to specific receptors on cells.

4. Prolonged Action

The successful introduction of oral prolonged action substances has stimulated

interest in the physical and chemical means of extending the therapeutic activity of a
drug administered by this route. Only in the past few years have clinical reports on
such formulations appeared in the medical literature. Concomitantly, questions have
been raised concerning in vitro and in vivo measurements of the release rate of the
active ingredient in preparations of this kind. The technique used for measuring the
release of active substance from sugar or enteric coated tablets does not necessarily
apply to these new forms, and modifications may be necessary. A critical review of
sustained action medication, with particular emphasis on the measurement of
pharmacological and therapeutic effects, appears appropriate at this time. Various
expressions have been used to describe oral sustained release preparations. Extended
action, sustained release, sustained action, oral repository, timed disintegration,
timed release, oral depot therapy, prolonged action, prolonged release, controlled
release and protracted release are examples of terms in current usage. At a recent
meeting of representatives of the major pharmaceutical manufacturing firms in the
United States, various suggestions were made for a definitive term other than timed
releasel. In this review article, the terms prolonged action and sustained release will
be used interchangeably. Several definitions have been offered in the literature for
prolonged action medication. Lang used the designation “prolonged action” for
formulations in which adequate measures provide a longer duration of therapeutic
effect of the drug substance than is usually achieved with classical preparations.
Theoretically, there would be an equilibrium in the body between the continuous
administration and the inactivation and elimination of the active substance within the
therepeutically optimal range of concentration. Abrahams and LinnelP have stated
that ideally an orally administered drug should be in such form that a single dose
would be continuously absorbed over an extended period of time thereby maintaining
a uniform optimal level in the tissues and avoiding unnecessarily high peak
concentrations as well as wasteful depressions. Blythe describes oral sustained
release preparations as those which “provide a sustained therapeutic effect by first
releasing a therapeutic dose, then gradually and continually releasing medication
over a prolonged period.”. He emphasises that sustained release is not to be confused
with individual doses, usually two or three, released at widely spaced intervals.
Micciche has referred to oral-prolonged action medications as those which have a
pre-established and controlled delayed release. This definition implies that the
 release pattern of the dosage form has been carefully determined and is consistently
reproducible. Ettore likewise defines an oral prolonged action dosage form as one
which permits a controlled release of the active drug, in regard to time, but adds the
proviso that the relationships between absorption, elimination or metabolism of the
drug should have already been studied. Blythe’s definition is based upon a
pharmaceutical dosage form while the others are more general. If we are to be guided
by these definitions, it is apparent that, before a suitable release pattern can be
established, the fate of the drug in the body must be thoroughly understood. In spite
of the long history of the use of drugs by absorption from the gastrointestinal tract,
the evolution of basic physiological understanding of the processes involved has
been surprisingly slow.

5. Repeat Action

Repeat-action tablets are prepared so that an initial dose of drug is released

immediately and a second dose follows later. Repeat-action forms usually contain
two single doses of medication, one for immediate release and the second for delayed
release. Two-layer tablets, for example, may be prepared with one layer of drug for
immediate release with the second layer designed to release drug later as either a
second dose or in an extended-release manner, separated by a slowly permeable
barrier coating. In general, the drug from the inner core is exposed to body fluids and
released 4 to 6 hours after administration. An example of this type of product is
Repetabs (Schering). Repeat-action dosage forms are best suited for treatment of
chronic conditions requiring repeated dosing. The drugs should have low dosage and
fairly rapid rates of absorption and excretion.

6. Controlled Release

Controlled-release systems also offer a sustained-release profile but, in contrast to

sustained-release forms, controlled-release systems are designed to lead to
predictably constant plasma concentrations, independently of the biological
environment of the application site. This means that they are actually controlling the
drug concentration in the body, not just the release of the drug from the dosage form,
as is the case in a sustained-release system. Another difference between sustained-
 and controlled-release dosage forms is that the former are basically restricted to oral
dosage forms whilst controlled-release systems are used in a variety of
administration routes, including transdermal, oral and vaginal administration.
Controlled release of drugs from a dosage form may be achieved by the use of so-
called therapeutic systems. These are drug delivery systems in which the drug is
released in a predetermined pattern over a fixed period of time. The release kinetics
is usually zero-order. In contrast to sustained-release systems, the dose in the
therapeutic systems is of less importance than the release rate from the therapeutic
system. Ideally the release rate from the dosage form should be the rate-determining
step for the absorption of the drug and in fact for the drug concentration in the
plasma and target site. However, controlled-release systems are not necessarily
target-specific, whichmeans that they do not ‘exclusively’ deliver the drug to the
target organ. This may be achieved by so-called targeted delivery systems which aim
to exploit the characteristics of the drug carrier and the drug target to control the
biodistribution of the drug. Picture below shows an idealised plasma concentration
versus time profile of a controlled-release dosage form.

7. Modified Release

Dosage forms are denned by the USP as those whose drug release characteristics of
time course and/or location are chosen to accomplish therapeutic or convenience
objectives not offered by conventional forms, whereas an extended-release (ER)
 dosage form allows a twofold reduction in dosing frequency or increase in patient
compliance or therapeutic performance. It is interesting to note that the USP
considers that the terms controlled release, prolonged release and sustained release
are interchangeable with extended release. From a biopharmaceutical perspective this
is not strictly a concern.

8. Sustained Release

These systems maintain the rate of drug release over a sustained period. For example,
if the release of the drug from the dosage form is sustained such that the release takes
place throughout the entire gastrointestinal tract, one could reduce Cmax and prolong
the time interval of drug concentration in the therapeutic range. This in turn may
reduce the frequency of dosing, for example from three times a day to once a day.
Sustained-release dosage forms achieve this mostly by the use of suitable polymers,
which are used either to coat granules or tablets (reservoir systems) or to form a
matrix in which the drug is dissolved or dispersed (matrix systems). The release
kinetics of the drug from these systems may differ: & Reservoir systems often follow
a zero-order kinetics (linear release as a function of time). & Matrix systems often
follow a linear release as a function of the square root of time.
 DAFTAR PUSTAKA

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Edition. Inggris: Churchill Livingstone.

Allen, L.V. & Ansel H.C. 2014. Ansel’s Pharmaceutical Dosage Forms and Drug
Delivery Systems Tenth Edition. Philadelpia: Lippincott Williams & Wilkins.

Ghosh, T. K., Jasti, B. R. 2005. Theory and Practice of Contemporary Pharmaceutics.

America: CRC Press.

Lazarius, Jack & Jack Cooper. 1959. Oral Prolonged Action Medicaments: Their
Pharmaceutical Control and Therapeutic Aspects. New Jersey: CIBA
Pharmaceutical Company.

Shargel, L., Yu, Andrew & Susanna Wu-Pong. 2012. Applied Biopharmaceutics &
Pharmacokinetics. New York: McGraw-Hill Companies.