SEDIAAN FARMASI SEMISOLID

Drs. Kosasih, M.Sc., Apt.

 RELEASE OF DRUGS
FROM EMULSION FORMULATION
FORMULATIONS
The main commercial use of emulsions is for the oral, rectal and
topical administration of oils and oil soluble drugs.
NDAHULUAN
Lipid emulsions are also widely used for intravenous feeding,
although the choice of emulgent is very limited and globule
size must be kept below 4 m diameter to avoid the
formation of emboli.

Quite often, however, the high surface area of dispersed oil

globules will enhance the rate of absorption of lipophilic
drugs.
 RELEASE OF DRUGS
FROM EMULSION FORMULATION
FORMULATIONS
The emulsion can also be used as a sustained release dosage
form.
NDAHULUAN
The i.m. injection of certain water-soluble vaccines
formulated as w/o emulsions can provide a slow release of
the antigen and result in a greater antibody response and
hence a longer-lasting immunity.

Other drugs have also been shown to have this effect,

the rate of release being dependent mainly upon the
oil/water partition coefficient of the drug and its rate of
diffusion across the oil phase.
 RELEASE OF DRUGS
FROM EMULSION FORMULATION
It is also possible toFORMULATIONS
formulate multiple emulsion systems in
which an aqueous phase is dispersed in oil droplets, which in
turn are dispersed NDAHULUAN
throughout another aqueous external
phase, producing a water-in- oil-in-water (w/o/w) emulsion.

These products can also be used for the prolonged release of

drugs that are incorporated into the internal aqueous phase.

These products have the advantage of exhibiting a lower

viscosity than their w/o counterparts and hence are easier to
inject.
 RELEASE OF DRUGS
FROM EMULSION FORMULATION
FORMULATIONS
Similarly, o/w/o emulsions can be formulated and are also
NDAHULUAN
under investigation as potential sustainedrelease bases.

Multiple emulsions, however, tend to be stable only for a

relatively short time, .....

although the use of polymers as alternatives to the

traditional emulsifying agents may improve their physical
stability (Florence andWhitehill 1982).
 KEY POINTS
Administration of drugs to the rectum and vagina may be
performed to treat local disorders, e.g. infection and
inflammation, or to achieve systemic absorption of the
therapeutic agent in situations where alternative routes of
drug administration are inappropriate.

Suppositories are the main class of rectal dosage forms;

however, creams, gels and foams are also used for this
purpose.

Pessaries, creams and gels are commonly used for the

delivery of therapeutic agents to the vagina.
 KEY POINTS
The strategies for the formulation of gels and creams for
rectal or vaginal administration are identical to those
described in previous chapters.

Suppositories and pessaries are semisolid or solid dosage

forms that are inserted into the rectum and vagina,
respectively.
Advice must be given to patients regarding their
administration.

Rectal and vaginal dosage forms are non-sterile formulations.

 Rectal dosage forms
Advantages
Rectal dosage forms may be successfully employed to provide
a local effect for the treatment of infection and inflammation,
e.g. haemorrhoids, proctitis.
Rectal dosage forms are used to promote evacuation of the
bowel (by irritating the rectum), to relieve constipation or to
cleanse the bowel prior to surgery.
Rectal dosage forms may be employed to provide systemic
drug absorption in situations where oral drug absorption is
not recommended. Examples of such applications include:
patients who are unconscious, e.g. in intensive care or
who are postoperative
 Rectal dosage forms
Advantages
patients who are vomiting, e.g. gastrointestinal infection,
migraine
gastroirritant drugs, e.g. non-steroidal anti-inflammatory
agents, particularly in chronic usage
drugs that are prone to degradation in the stomach
drugs that are erratically absorbed from the upper
gastrointestinal tract
 Rectal dosage forms
Advantages
administration of drugs that are extensively first-pass
metabolised.

If administered correctly, the therapeutic agent is

absorbed directly into the systemic circulation, thereby
avoiding direct entry into the liver.

It should be noted that any drug that is absorbed

following oral administration would be systemically
absorbed when administered rectally.
 Rectal dosage forms
Advantages
Rectal dosage forms may be employed to provide local
treatment of diseases of the colon, e.g. Crohns disease,
ulcerative colitis.

Following advice from the pharmacist, the administration of

the rectal and vaginal dosage forms may be easily performed
by the patient.
 Rectal dosage forms
Disadvantages
In certain countries, especially the USA and the UK, the rectal
dosage forms are generally unpopular, especially for systemic
administration of therapeutic agents, whereas the opposite is
true in European countries.
Specialist advice is required concerning the administration of
dosage forms.
The absorption of therapeutic agents from the rectum is slow
and prone to large intrasubject and intersubject variability.
The presence of faeces within the rectum considerably
affects both the rate and extent of drug absorption.
 Rectal dosage forms
Disadvantages
Rectal administration of therapeutic agents may result in the
development of local side-effects, in particular proctitis.

The industrial manufacture of suppositories is more difficult

than for other common dosage forms.
 Figure 1.
Diagrammatic representation of the gastrointestinal tract,
with particular emphasis on the rectum (see insert).
(Adapted from Human Physiology en.wikibooks.org.)
 Rectal dosage forms
The main physiological features of the rectum that are related
to drug delivery and hence to the formulation of rectal
products are as follows:
The length of the rectum is circa 1520 cm. The rectum is
joined to the sigmoid colon at the top and to the anus.
The rectum is divided into two sections:
(1) the anal canal;
(2) the ampulla. The ampulla is the larger of the two sections
(approximately four times larger than the anal canal).
Faeces are stored in the ampulla and excreted through
the anus (a circular muscle) via the anal canal.
 Rectal dosage forms
Following absorption from the rectum, the therapeutic agent
enters the haemorrhoidal veins.
Blood from the upper haemorrhoidal vein enters the portal
vein, which flows into the liver, where drug metabolism
occurs.
Conversely, blood in the middle and lower haemorrhoidal
veins enters the general circulation (Figure 2.).
 Figure 2.
Diagrammatic representation of blood flow into and from the
rectum. (Adapted from http:// www.
instantanatomy.net/diagrams/AB073.jpg.)
 Rectal dosage forms
The wall of the rectum is composed of an epithelial layer that
is one cell thick.

Two cellular types exist:

(1) cylindrical cells;
(2) goblet cells the latter are responsible for the secretion
of mucus.
There are no villi (or microvilli).

When empty the rectum contains circa 3 ml of mucus, spread

over a rectal surface area of approximately 300 cm2.
 Rectal dosage forms
The pH within the rectum is essentially neutral with minimal
buffering capacity.
Therefore, due to the inability of the fluids within the rectum
to alter the degree of ionisation, the salt form of the drug is
an important determinant of the resulting local efficacy
and/or systemic absorption.
The presence of faecal matter will markedly affect both the
dissolution of the drug in the rectal fluids and the subsequent
absorption of the drug into the systemic circulation.
 Rectal dosage forms
As detailed above, the fate of the absorbed drug is dependent
on the area of the rectum from which absorption has
occurred.
Drugs that are absorbed into the inferior and middle
haemorrhoidal veins will enter the circulation via the inferior
vena cava and will subsequently avoid direct exposure of the
drug to, and hence metabolism by, the liver.
Absorption into the upper (superior) haemorrhoidal vein will
result in entry into the liver (and subsequent metabolism) via
the portal vein.
 Rectal dosage forms
Examples of the classes of drugs that are administered by the
rectal route for systemic absorption include:
antiemetics (e.g. Prochlorperazine)
analgesics (e.g. oxymorphone hydrochloride)
anti-inflammatory agents (e.g. Indometacin)
ergot alkaloids.

There are no esterases or peptidases in the rectal fluid.

Local muscle activity within the rectal wall may influence the
rate of dissolution of solid dosage forms within the rectum,
i.e. suppositories.
 Rectal dosage forms
Factors affecting the rectal absorption of therapeutic agents
The process by which drugs are absorbed into the systemic
circulation involves the dissolution of the drug in the rectal
fluids (which is often preceded by the dissolution/melting of
the dosage form), diffusion of the drug through the rectal
fluids to the rectal mucosa and then absorption.
There are various factors that affect the rate and extent of
drug absorption, as follows.
1. Site of absorption within the rectum
As highlighted previously, the site of absorption will affect the
fate of the therapeutic agent within the blood stream.
Therefore
 Rectal dosage forms
1. Site of absorption within the rectum
Therefore the metabolism of therapeutic agents will depend
on the location of the dosage form.
It should be noted that it is difficult to ensure that drug
absorption occurs exclusively via the inferior and middle
haemorrhoidal veins and, .....
therefore, first-pass metabolism of therapeutic agents will
occur following rectal administration
(although the extent of this is markedly lower when compared
to drug absorption following oral administration).
 Rectal dosage forms
2. The partition coefficient and degree of ionisation of the
therapeutic agent

Some rectal products are lipophilic (see later in this chapter)

and therefore if the therapeutic agent is also lipophilic, the
release of the drug will be slow and the solubility of the drug
in the rectal fluids will be low
(a factor that is compounded by the low volume of the latter).

Conversely, the use of (dispersed) hydrophilic drugs in

lipophilic bases is preferred, as these would exhibit a greater
thermodynamic tendency to dissolve in the rectal fluid.
 Rectal dosage forms
2. The partition coefficient and degree of ionisation of the
therapeutic agent
It should be noted that the limited volume of fluid in the
rectum affects both the rate and extent of drug dissolution
and, therefore, increasing the drug loading in suppositories
does not enhance drug absorption.
The reader will be aware that the degree of ionisation of
therapeutic agents affects the resultant absorption by
biological membranes, as absorption requires the presence of
the unionised form of the drug.
Commonly the pH and buffer capacity of biological fluids will
control the degree of ionisation and hence the absorption of
the therapeutic agent.
 Rectal dosage forms
2. The partition coefficient and degree of ionisation of the
therapeutic agent
However, the poor buffer capacity of the rectal fluid results in
the inability of this fluid to control the pH and hence the
ionisation.
Therefore, the salt form of the therapeutic agent effectively
controls the degree of ionisation.
3. The particle size of the dispersed active agent
If the formulation is composed of an active agent that has been
dispersed in the appropriate formulation base/vehicle, e.g. a
hydrophilic drug dispersed in a lipophilic base or vice versa, the
rate of dissolution of the drug is inversely proportional to the
particle size of the dispersed active agent.
 Rectal dosage forms
3. The particle size of the dispersed active agent
A reduction in particle size of the dispersed therapeutic agent
will also affect the physical stability of the formulation, as
previously discussed for suspensions.
4. The physicochemical properties of the formulation base
One of the main criteria for rectal formulations is the ability
to release the drug.
Any interactions between the formulation and dosage form
effectively delay release and hence local action/absorption.
This interaction may be specific, e.g. resulting from a specific
interaction between the drug and the vehicle, or may be non-
specific, in which lipophilic drugs are dissolved in lipophilic
bases.
 Rectal dosage forms
4. The physicochemical properties of the formulation base
The latter concern may be obviated by choice of drug salt.
In addition, it is important to ensure that the formulation is
non-irritant to the rectal mucosa as irritation frequently
results in defecation and hence removal of the dosage form
before the required mass of drug has been released.

5. Formulation of rectal dosage forms

There are several formulation types that are used rectally,
including creams, ointments, gels, solutions and
suppositories.
 Rectal dosage forms
5. Formulation of rectal dosage forms
The formulation considerations for semisolid preparations
(creams, ointments, gels) and solutions that are designed for
rectal use are similar to those that are formulated for
nonrectal use.
Therefore, for more information on these aspects the reader
should consult the earlier chapters.
As a result the remainder of this section will address the
formulation of suppositories.
 Rectal dosage forms
Formulation of suppositories
Suppositories are solid-dosage forms that are inserted into
the rectum where they undergo softening, melting or
dissolution to liberate the therapeutic agent.
Suppositories may also be inserted into the vagina and other
accessible body cavities, e.g. the urethra and, as such, are
available in a wide range of sizes and shapes, as depicted in
Figure 3.
The typical weight range for suppositories is 14 grams, with
the 2-gram suppository being the commonly used size.
 Rectal dosage forms
Formulation of suppositories
The smallest suppositories are mainly reserved for use in
children, whereas the largest size may be administered to
adults, e.g. glycerin suppositories that are used to relieve
constipation in adults.
Suppositories are tapered at one end (to aid insertion) and
are frequently wider in the middle before tapering towards
the other end
(thereby aiding retention in the rectum and enabling the
suppository to be pressed forward by the anal sphincter).
The drug loading of suppositories ranges from 0.1 - 40% w/w.
 Rectal dosage forms
Formulation of suppositories
In general, suppositories are composed of an inert base into
which the therapeutic agent is incorporated (dissolved/
dispersed).
The physicochemical properties of both the therapeutic agent
and suppository base are important determinants of the
clinical and non-clinical performance of suppositories.
The role of the solubility, salt type and particle size on the
dissolution and hence pharmacological activity of rectal
dosage forms, e.g.
Suppositories, has been addressed earlier in this chapter.
 Rectal dosage forms
Formulation of suppositories
The next subsection describes the types and physicochemical
properties of suppository bases.

Figure 3. Examples of the different shapes and sizes of

suppositories. Taken from Allen L V Jr (2008) Suppositories.
London: Pharmaceutical Press.