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SALMAN BIN ABDULAZIZ UNIVERSITY
COLLEGE OF PHARMACY
Dr. Mohammad Khalid Anwer
e-mail:- [email protected]
A suppository is a medicated or non medicated solid dosage form
generally intended for use in the rectum, vagina and urethra.
Drugs may be administered in suppository form for either local or
systemic effects. Such action depends on the nature of the drug,
its concentration, and the rate of absorption.
 Emollients, astringents, antibacterial agents, steroids, and local
anesthetics are dispensed in suppository
for treating local conditions
 Analgesics, antispasmodics, sedatives,
tranquilizers, and antibacterial agents
are dispensed in suppository for systemic action
Types and shapes of suppositories
1. Rectal suppositories are tapered to
resemble a torpedo shape. weigh
about 2 g for adults and 1 g for
Children.
2.Vaginal suppositories molded in the
globular or oviform shape, or compressed
on a tablet press into modified conical
shapes. weigh about 3 to 5 g.
3.Urethral suppositories called bougies, are
pencil shaped and pointed at one extremity.
for males weigh about 4 g each and are
100 to 150 mm long;
for females, they are 2 g each and usually
60 to 75 mm in length.
Factors Affecting Drug Absorption from
Rectal Suppositories
Physiologic Factors
Many drugs cannot be administered orally Why?
 Affected by the digestive juices
 Their therapeutic activity is modified by the liver
enzymes after absorption from the small intestine.
More than (50 to 70%) of rectally administered drugs can
be absorbed from the anorectal area into the general
circulation and still retain therapeutic values. Why?
1
The lower hemorrhoidal veins surrounding the colon
and rectum enter into the inferior vena cava and thus
bypass the liver.
 The upper hemorrhoidal vein does
connect with the portal veins leading
to the liver.
 The lymphatic circulation helps also
in absorbing a rectally administered
drug and in diverting the absorbed
drug from the liver.
2 The pH of the rectal mucosa has a rate-controlling
role in drug absorption.
The colon has a pH of ≈ 6.8, with no buffer
capacity, thus the dissolving drugs determine
the pH in the ano-rectal area.
 Colonic lumen is permeable to the unionized forms of
drugs. Thus, weaker acids and bases are more readily
absorbed than the stronger, highly ionized ones. Thus,
the absorption of a drug would be enhanced by a change
in the pH of the rectal mucosa that would increase the
proportion of unionized drug.
So absorption of acidic drugs can be increased when
the pH of the surrounding fluids was lowered.
The absorption of salicylic acid rises from 12% at a pH
7 to 42% at pH 4. In contrast, with a basic drug like
quinine, which becomes more ionized at the lower pH
values,
the absorption is decreased
from 20% at pH 7 to 9% at pH 4.
3
The diffusion of the drug to the site on the
rectal mucosa at which absorption occurs.
The diffusivity is influenced by:
 The nature of the medicament, such as the presence of
surfactant or the water-lipoidal solubility of the drug
 The physiologic state of the colon (the amount and
chemical nature of the fluids and solids present).
 The state of the anorectal membrane. This membranous
wall is covered with a relatively continuous mucous
blanket, which can act as a mechanical
barrier for the free passage of drug through
the pore space where absorption occurs.
Physicochemical Characteristics o f the Drug
Drug in vehicle- Drug in colon fluidsAbsorption through the rectal mucosa
drug absorption from the anorectal area
1. Release the drug from the suppository base.
2. Distribute by the surrounding fluids to sites of absorption
3. Dissolve in the fluids
4. Contact of the drug with the lumen walls, and to a large
number of absorption sites.
Physicochemical Characteristics of the Base
For Fatty Bases:
• The
absorption rate is faster from fatty bases having a
lower melting range than from those with higher melting
ranges
• Since
fatty bases may harden for several months after
molding, this rise in melting range certainly would affect
absorption
For Polyethylene Glycol Bases
•The absorption rate increases along with hydroxyl values.
The absorption rate is faster as the molecular mass of the
polyethylene glycols (PEGs) used increased.
Specifications for suppository bases
1. Origin and Chemical Composition.
Either
entirely
natural,
synthetic
or
modified
natural
products.
Physical or chemical incompatibilities of the base with the
other constituents may be predicted if the exact formula
composition is known, including preservatives, antioxidants
and emulsifiers.
2. Melting Range.
Since fatty suppository bases are complex
mixtures of triglycerides and therefore do not
have sharp melting points, their melting
characteristics are expressed as a range indicating the
temperature at which the fat starts to melt and the
temperature at which it is completely melted.
3. Solid-Fat Index (SFI).
A base with a sharp drop in solids over a short temperature
span proves brittle if molded too quickly. This type of base
requires a reduced differential between mold temperature
and mass temperature for trouble-free molding. Suppository
hardness can be determined by the solids content at room
temperature. Since skin temperature is about 32°C, one can
predict a product that would be dry to touch from a solids
content over 30% at that temperature.
4. Hydroxyl Value.
This is a measure of unesterified
positions on glyceride molecules
and reflects the monoglyceride
and diglyceride content of a fatty
base. The number represents the
milligrams of KOH that would
neutralize the acetic acid used to
acetylate 1 g of fat.
5. Solidification Point.
Is the time required for solidifying the base when it is
chilled in the mold. If the interval between the melting range
and solidification point is 10°C or more, the time required for
solidification may have to be shortened by refrigeration to
produce a more efficient manufacturing procedure.
6. Saponification Value.
Is the number of milligrams of potassium hydroxide
required to neutralize the free acids and saponify the esters
contained in 1 g of a fat is an indication of the type (mono-,
di-, or tri-) glyceride, as well as the amount of glyceride
present.
7. Iodine Value.
Is the number of grams of iodine that
reacts with 100 g of fat or other unsaturated material. The
possibility of decomposition by moisture, acids, and oxygen
(which leads to rancidity in fats) increases with high iodine
values.
8. Water Number.
Is the amount of water, in grams, that can be incorporated in
100 g of fat.
The "water number" can be increased by the addition of
surface active agents, monoglycerides, and other emulsifiers.
9. Acid Value.
Is the number of milligrams of potassium hydroxide required
to neutralize the free acid in 1 g of substance. Low "acid
values" or complete absence of acid are important for good
suppository bases.
Free acids complicate formulation work, because they react
with other ingredients and can also cause irritation when in
contact with mucous membranes.
Types of Suppository Bases
The Ideal Suppository Base for long shelf-life
1. Having reached equilibrium crystallinity.
The majority of components melt at rectal
temperature 36°C
Bases with higher melting ranges may be employed for:
eutectic mixtures, addition of oils, balsams, and
suppositories intended for use in tropical climates.
2. Completely nontoxic and nonirritating to sensitive
and inflamed tissues.
3. Compatible with a broad variety of drugs.
4. Has no metastable forms.
5. Shrinks sufficiently on cooling to release itself
from the mold without the need for mold
lubricants.
6. Has wetting and emulsifying properties.
7. High water number.
i.e. a high percentage of water can be incorporated in it.
8. Stable on storage.
i.e. does not change color, odor, or drug release pattern.
9. Can be manufactured by molding by either hand,
machine, compression, or extrusion.
If the base is fatty, it has the following
additional requirements:
10. Acid value below 3
11. Saponification value ranges from 200 to 245
12. Iodine value less than 7
13. The interval between "melting point (34oC)" and
"solidification (32oC) point" is small
14. Low melting ranges (30- 34oC) for incorporating drugs
that increases the melting range of the base.
Ex. Silver nitrate or lead acetate
High melting ranges (37-41°C) for incorporating drugs
that lower melting points of the base.
Ex. Camphor, chloral hydrate, menthol, phenol, thymol,
and several types of volatile oils or for formulating
suppositories for use in tropical climates.
Oleogenous Suppository Bases
Cocoa Butter (Theobroma Oil)
Cocoa butter is a yellowishwhite, solid, brittle fat.
Smells and tastes like chocolate.
Its melting point lies between 30°C and 35°C.
Its iodine value is between 34 and 38.
Its acid value is no higher than 4.

ADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE
 The most widely used suppository base
 It satisfies many of the requirements for an ideal base
 Safe, non reactive and melts at
body temperature.
DISADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE
 Cocoa butter does not contain emulsifiers and
therefore does not take up large quantities of
water (maximum 20 to 30 g of water to 100 g
of cocoa butter).
The addition of emulsifiers such as Tween 60 (5 to 10%)
increases the water absorption considerably. Emulsifiers
also help to keep insoluble substances suspended in the fat.
Suspension stability is further obtained by the addition of
materials (aluminum monostearate, silica) that give melted
fats thixotropic properties. There is always the possibility
that the suppositories containing these additives will harden
on
storage.
Therefore,
prolonged,
observations are recommended.
careful
stability
Low
contractility
during
solidification
causes
the
suppositories to adhere to molds and necessitates the use of
mold release agents or lubricants.
 Drugs as volatile oils, creosote, phenol, and chloral hydrate
lower the melting point of cocoa butter.
To correct this condition, wax and spermaceti are commonly
used.
 Cacao butter exhibits different polymorphisms each
has different melting points
Cocoa butter is primarily a triglyceride.
A phenomenon due to the high proportion of
unsaturated triglycerides is that it exhibits
polymorphism (the property of existing in
different crystalline forms).
Each of the different forms of cocoa butter has different
melting points, and different drug release rates.
When cocoa butter is heated above its melting temperature
(36°C) and chilled to its solidification point (below 15°C),
immediately after returning to room temperature this cocoa
butter has a melting point of about 24°C, approximately 12°
below its original state.
Cocoa butter is thought to be capable of existing
in four crystalline states:
1.The α form
Obtained by suddenly cooling melted cocoa butter to 0°C.
It melts at 24°C
2. The β form
Crystallizes out of the liquefied cocoa butter with stirring
at 18 to 23°C.
Its melting between 28 and 31°C.
3. The β’ form
Changes slowly into the stable β form which melts
between 34 and 35°C.
This change is accompanied by a volume contraction.
γ
4. The form
Melting at 18°C
Obtained by pouring a cool (20°C) cocoa butter, before it
solidifies, into a container which is cooled at deepfreeze
temperature.
The formation of various forms of cocoa butter depends on:
The degree of heating
The cooling process
The conditions during this process.
At temperatures below 36°C, negligible amounts of the
unstable forms are obtained
But prolonged heat above that critical temperature causes
the formation of the unstable crystals with resulting
lowered melting points. Thus, prolonged heating in the
process of melting the fats must be avoided
The reconversion to the stable 3 form takes one to four
days, depending on the storage temperature, the higher the
temperature, the faster the change.
The formation of the unstable forms can be avoided by:
1. If the mass is not completely melted, the remaining
crystals prevent the formation of the unstable form.
2. Small amounts of stable crystals added to the melted
cocoa butter accelerate the change from the unstable to
the stable form; this process is called “Seeding."
3. The solidified melt is tempered at temperatures between
28 and 32oC for hours or days, causing a comparatively
quick Change from the unstable to the stable form.
Cocoa Butter Substitutes
Cocoa butter substitutes maintain the desirable properties
of cocoa butter and eliminate the undesirable ones.
Treatment o f Vegetable Oils to Produce Suppository Bases
Synthetic or natural oils as vegetable oils as coconut or palm
kernel oil are modified by:
Esterification, hydrogenation and fractionation at different
melting ranges to obtain the desired product.
Hydrophilic Suppository Bases
Glycerin Suppositories
Glycerinated gelatin suppositories do not melt at body
temperature but dissolve in the secretions of the body cavity
in which they are inserted (vaginal or rectal).
Solution
time
is
regulated
by
the
proportion
of
gelatin/glycerin/water used, the nature of the gelatin used,
and the chemical reaction of the drug with gelatin.
Glycerinated gelatin suppositories support mold or bacterial
growth, thus, they are stored in a cool place and often
contain agents that inhibit microbial growth.
Because glycerin is hygroscopic, these suppositories are
packaged in materials that protect them from environmental
moisture.
The Polyethylene Glycols
(Carbowax and Polyglycols)
Long-chain polymers of ethylene oxide have the general
formula
HOCH2 (CH2OCH2)X CH2OH
 When their average molecular weight ranges from 200 to
600 they exist as liquids, and as wax-like solids when
their molecular weights are above 1000.
 Their water solubility, hygroscopicity, and vapor pressure
decrease with increasing average molecular weights.
 The wide range of melting points and solubilities makes
possible to formulate suppositories with various degrees
of heat stability and different dissolution rates.
Several combinations of polyethylene glycols have been
prepared for suppository bases having different physical
characteristics.
Base 1
Polyethylene glycol 1000
Polyethylene glycol 4000
96 %
4 %
This base has low-melting and require refrigeration.
It is useful when rapid disintegration is desired.
Base 2
Polyethylene glycol 1000
Polyethylene glycol 4000
75 %
25 %
More heat stable than Base 1 and stored at higher
temperatures.
It is useful when a slow release of active ingredients is
desired.
ADVANTAGES of POLYETHYLENE GLYCOL
as SUPPOSITORY BASE
 Polyethylene
glycol suppositories do not require a mold
lubricant and are easier to prepare than cocoa butter
suppositories.
 They
are physiologically inert, do not hydrolyze or
deteriorate and do not support mold growth.
DISADVANTAGES of POLYETHYLENE GLYCOL
as SUPPOSITORY BASE
 Most
patients do feel discomfort from the use of these
suppositories, because this type of Bases cause irritation
"sting“ to mucous membranes when water drawn from the
mucosa. This irritation may be eliminated by dipping in water
before insertion or by addition of 10% water to facilitate
solution of the suppository after insertion.
Water-Dispersible Bases
These
are
nonionic
surface
active
materials,
related
chemically to the polyethylene glycols.
The surfactants most commonly used in suppository
formulations are the polyoxyethylene sorbitan fatty acid
esters (Tween), the polyoxyethylene stearates (Myrj) and
the sorbitan fatty acid esters (Span and Arlacel). These
surface active agents may be used alone, blended, or used
in combination with other suppository vehicle materials to
yield a wide range of melting points and consistencies.
ADVANTAGES of WATER-DISPERIBLE
BASES as SUPPOSITORY BASE
 Can be used for formulating both water-soluble and oilsoluble drugs.

Can be stored and handed at elevated temperatures

Have broad drug compatibility.

Nonsupport of microbial growth, nontoxic and not cause
sensitivity.
DISADVANTAGES of WATER-DISPERIBLE
BASES as SUPPOSITORY BASE

Caution must be taken in the use of surfactants with drugs
due to the increase in the rate of drug absorption.

These surface active agents can show interaction with
drugs and a consequent decrease in therapeutic effects.
Compressed Tablet Suppositories
Rectal suppositories usually are not compressed as
tablets, because the amount of liquid in the rectal cavity is
insufficient for tablet disintegration.
Effervescent tablets aid disintegration, as carbon dioxide
releasing laxative suppositories.
This compressed rectal suppository is coated
with water-soluble polyethylene glycol to aid
in insertion into the rectum.
The compressed tablet for vaginal use weighing about 3 g
with almond shape to ease insertion. The moisture level of
the vagina is sufficient for disintegration and dissolution.
A typical vaginal tablet contains active ingredients, with
boric and/or phosphoric acid for adjusting the acidity of
the vagina to pH 5. Vaginal suppositories are usually used
for systemic or topical therapy, as in the treatment of
vaginitis, or as a spermatocide.
Soft gelatin capsules filled with liquid or solid drugs used
for vaginal use.
The suppositories are non-melting,
but dissolve in body fluids.
Formulation of Suppositories
Hygroscopicity
Glycerinated gelatin suppositories are hygroscopic, they
lose moisture by evaporation in dry climates and absorb
moisture under conditions of high humidity.
Polyethylene glycol bases are hygroscopic, the rate of
moisture change in polyethylene glycol bases depends on
humidity, temperature and on the chain length of the
molecule.
As
the
molecular
hygroscopicity decreases.
weight
increases,
the
Water in Suppositories
Use of water as a solvent for incorporating substances in
suppository bases should be avoided for the following
reasons.
1. Water accelerates the oxidation of fats.
2. If the water evaporates, the dissolved substances
would crystallize out.
3. Reactions between ingredients are more likely to occur
in the presence of water.
4. Bacterial or fungal growth necessitates the addition of
bacteriostatic agents as parabens.
Viscosity
The viscosity of the melted suppository mass is important
in the manufacture of the suppository and to its behavior in
the rectum after melting.
Melted cocoa butter and some of its substitutes have low
viscosities,
whereas
the
glycerinated
gelatin
and
polyethylene glycol type base have viscosities considerably
higher than cocoa butter.
In the manufacture of suppositories made with lowviscosity bases, extra care must be exercised to avoid the
sedimentation of suspended particles. Poor technique can
lead
to
nonuniform
suppositories,
particularly
in
the
distribution of active ingredients.
To prevent segregation of particles suspended in molten
bases, the well-mixed mass should be handled at the lowest
temperature necessary to maintain fluidity, constantly
stirred without entrapping air, and quickly solidified in the
mold.
The following approaches may be taken to overcome the
problems caused by use of low viscosity bases.
1. Use a base with a more narrow melting range that is
closer to body temperature.
2.The
inclusion
of
approximately
2%
aluminum
monostearate not only increases the viscosity of the fat base
considerably, but also aids in maintaining a homogeneous
suspension of insoluble materials. Cetyl, stearyl, or myristyl
alcohols or stearic acid are added to improve the consistency
of suppositories.
Brittleness
 Suppositories made from cocoa butter are elastic and do
not fracture.
 Synthetic fatty bases with a high degree of hydrogenation
are more brittle. Fracturing of the suppository made with
such bases is induced by rapid chilling (shock cooling) of
the melted bases in an extremely cold mold.
 Brittle suppositories have problems in manufacturing,
handling and wrapping.
To overcome this difficulty, the temperature differential
between melted base and mold should be as small as
possible. Addition of a small amount of Tween 80, Tween 85,
fatty acid monoglycerides, castor oil, glycerin, or propylene
glycol increases its plasticity and renders it less brittle.
Density
To calculate the amount of drug per suppository,
the density of the base must be known.
The volume of the mold cavity is fixed, and therefore, the
weight of the individual suppository depends on the density
of the mass.
Knowledge of the suppository weight can be obtained
from a given mold and density of the chosen base; the active
ingredients can then be added to the bulk base in such an
amount that the exact quantity of drug is present in each
molded suppository.
If volume contraction occurs in the mold
during cooling, additional compensation
must be made to obtain the proper suppository weight.
Thus, density alone cannot be the sole criterion for
calculating suppository weight per fixed volume mold.
When volume contraction occurs, the suppository weight is
determined empirically by small batch runs.
Volume Contraction
This phenomenon occurs in many melted
suppository bases after cooling in the mold.
The results are manifested in the following two ways.
1. Good mold release. This is caused by the mass pulling away
from the sides of the mold. This contraction facilitates the
removal of the suppositories from the mold, eliminating the
need for mold release agents.
2. Contraction hole formation at the open
end of the mold. This undesirable feature
results in lowered suppository weight and
imperfect appearance of the suppository.
The contraction can be eliminated by pouring a mass
slightly above its congealing temperature into a mold
warmed to about the same temperature. In volume
production using standard molds, where adequate control
of temperature may not be feasible, the mold is overfilled
so that the excess mass containing the contraction hole can
be scraped off.
Lubricants or Mold Release Agents
Cocoa butter adheres to suppository
molds because of its low volume contraction.
These suppositories are difficult to remove from the molds,
and various mold lubricants or release agents must be used
to overcome this difficulty.
Mineral oil, an aqueous solution of sodium lauryl sulfate,
various silicones, alcohol, and tincture of green soap are
examples of agents employed for this purpose.
They are applied by wiping, brushing, or spraying. The
release
improved
of
suppositories
by
coating
fluoroethylene (Teflon).
from
the
damaged
cavities
with
molds
was
polytetra-
Rancidity and Antioxidants
Confusion may take place between the acidity of fats with
rancidity.
The presence of free fatty acids is no indication of rancidity
or that such a product may become rancid.
Rancidity results from the autoxidation and decomposition
of unsaturated fats into low and medium molecular weight
saturated and unsaturated aldehydes, ketones and acids,
which have strong, unpleasant odors.
The
lower
the
content
of
unsaturated
fatty
acid
constituents in a suppository base, the greater is its
resistance to rancidity.
Since
this
reaction
begins
with
the
formation
of
hydroperoxides, the measure of autoxidation is the
peroxide value (active oxygen) which is a measure of the
iodine liberated from an acidified solution of potassium
iodide by "peroxide oxygen" of the fats.
Examples of effective antioxidants:
Phenols: such as m- or p-diphenols; α-naphthol;
Quinones: such as hydroquinone or β-naphthoquinone;
Tocopherols: particularly the α and β forms;
Gossypol present in cottonseed oil;
Sesamol present in sesame oil;
Propyl gallate and gallic acid;
Tannins and tannic acid;
Ascorbic acid and its esters;
Butylhydroxyanisole
(BHT).
(BHA)
and
butylhydroxytoluene
An Approach in Formulating Suppositories
The important considerations of the formulator are:
Is the medication intended for local or systemic use?
Is the site of application rectal, vaginal or urethral?
Is the desired effect to be quick or slow and prolonged?
Preliminary suppository bases to be studied are first
evaluated by measuring drug availability from the
suppository in water at 36 to 37°C.
Availability and cost of the suppository bases
Stability of both active ingredients and base at 4°C and
room temperature.
Ease of molding and release in the manufacturing
equipment.
Toxicity (irritancy) and drug availability are measured in
animals before the medication is ready for human
clinical trials.
Manufacture of Suppositories
Three methods are used in preparing suppositories:
Molding by hand
Compression molding
Pour molding
Compression Molding
A
more
uniform
and
pharmaceutically
elegant
suppository can be made by compressing the cold mass
into a desired shape.

A handturned wheel pushes a piston against the
suppository mass contained in a cylinder, so that the
mass is extruded into molds (usually three).
Pour Molding
The most commonly used method for producing
suppositories on both a small and a large scale.
First, the base material is melted, preferably on a water or
steam bath to avoid local overheating
Then the active ingredients are either emulsified or
suspended in it.
Finally, the mass is poured into cooled metal molds, which
are usually chrome or nickel-plated.
Packaging of Molded Suppositories
Suppositories must be packaged so that each suppository
is overwrapped, or they must be placed in a container in
that they do not touch each other.
Suppositories usually are foiled in tin,
aluminum, paper and plastic strips.
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