Suppositorie

s
Definitio
n
 Suppositories are solid, uniformly medicated conical or torpedo
shaped formulations intended for insertion into body orifices where
they melt, soften or dissolve, release medicaments and exert local
or systemic effects.

 The term came from the Latin word ‘supponere’ meaning ‘to place
under’.

 Thus, both linguistically and therapeutically they are meant to be

placed under the body as into the rectum.
Feature
sCommonly used rectally, vaginally and occasionally urethrally.


 They have variable shapes and weights depending on the density of the base
and medicaments.

 The shape and size of a suppository such that it is easily administered into the
intended orifice without causing undue distension.

 Once inserted it mist be retained for the appropriate period and should not
have any irritating or toxic properties.

 The medicaments should be intended for local action e.g. for haemorrhoids or
other anorectal conditions or for systemic actions including analgesia, anti-
inflammatory, tranquilising effects.

 Should be stable on the storage i.e. does not change color, odor or drug
release pattern.
Reasons for choosing rectal route for drug
administration:
(Advantages)
 When the patient is not able to make use of the oral route e.g. nauseating or
unconscious; the patient may have a problem with the GI tract, then this
route is beneficial.
 When the drug is nauseous, or in postoperative cases.
 For several categories of patients, such as very young, very old or
mentally
disturbed, may use rectal route other than oral route.
 When oral intake may cause GI side effects for example produces local
irritation, this route may be used.
 When the drug is unstable in the pH of the GIT, or susceptible to the
enzymatic attack in the GIT.
 To avoid the first pass metabolism in liver after absorption.
 Drugs with altered taste can be administered rectally.
 The rectal route is used in different therapies, intended either for
local/systemic
effect.
 Useful for rapid and direct effect in rectum.
 Prolonged effect of drugs can be obtained.
Disadvantages of rectal
route
 Slow & sometimes incomplete absorption.

 Small absorption area because the surface area of the rectum is small and
also
it is not a natural absorption organ.

 The fluid content of the rectum is less than that of small intestine and this
may
cause pain and produce problems with the dissolution of some drugs.

 Some drug may be degraded by the microbial flora present in the rectum.

 Large-scale production of suppositories is problematic & a suitable shelf-life

is
not achieved.

 Generally, it is not the route of first choice.

 Anatomy and physiology of
rectum
 The rectum is about 15 to 20 cm long.
 It hooks up with the sigmoid colon and with the anal canal.
 It is a hollow organ with a relatively flat wall surface.
 It dose not have villi and have only three major folds, the rectal
valves.
 The terminal 2 to 3 cm of the rectum is called the anal canal.
 The opening of the anal canal to the exterior is called the anus.
 Rectum contains (about 2 to 3 mucous, which has a pH
of 7.4
buffering capacity.
 The rectal tissues are drained by the inferior, middle and superior
haemorrhoidal veins, but only the superior vein connects with the
Anatomy and physiology of
rectum
Absorption of drugs from the
rectum
 Medicaments absorbed in the lower part of the rectum are
delivered directly into the systemic circulation, thus avoiding
any first-pass metabolism.
 However, it has been found that suppositories can settle high
enough in the rectum to allow at least some drug absorption
into the superior vein.
 Thus keeping the drug in the lower part of the rectum would
be advisable.
Absorption of drugs from the
rectum
 Insertion of a suppository into the rectum leads to
the systemic or local bioavailability of the drug.
 Suppository will either dissolve in the rectal fluid or melt
on the mucouslayer.
 Since the volume of rectal fluid is so small,
complete dissolution of the base require extra water.
 Drugs in the suppository diffuse out & absorption will
be passive diffusion.
Location of
suppository
 Absorption of drugs from the
rectum
3 separate veins

Lower Middle Upper

haemorroidal vein haemorroidal vein haemorroidal vein

Drain directly into the general Drains into the portal vein,
circulation which flows to the liver
Factors affecting drug absorption from rectal
suppositories
1. Physiologic factors
The human rectum is approximately 15-20 cm in the length, when empty
of fecal material; it contains 2-ml of inert mucous fluid. In resting state,
the rectum is non motile. There is no villa or microvillus on rectal
mucosa. Physiological factors affecting drug absorption from rectal
suppositories include:
a.pH and lack of buffering capacity of the rectal fluids: Rectal fluids
are neutral (pH 7-8), have no effective buffer capacity. The barrier
separating colon lumen from the blood is preferentially permeable to
the unionized forms of drugs, thus absorption of drug would be
enhanced by change in pH of the rectal mucosa to one that increase the
proportion of unionized drugs.
b.Properties of rectal fluid & it’s amount: The quantity of fluid
available for drug dissolution is very small (approximately 3 ml). Thus
the dissolution of slightly soluble substances is the slowest step in the
absorptive process.
c. Colonic content: When systemic effect are desired from suppository
greater absorption may be expected from a rectum that is void than that
with fecal matter. An evacuation enema maybe administered before
insertion of a suppository. Diarrhea, colonic obstruction and tissue
dehydration influence the rate & degree of drug absorption from rectum.
d. Circulation route:
Drugs absorbed rectally partially by pass portal circulation, thereby
enabling drug destroyed in liver to exert systemic effect. Depending on
the height at which absorption occurs at rectum, the drug passes into
inferior, middle or superior hemorrhoid veins. The inferior is nearest to
the anus, the upper hemorrhoid vein —> portal circulation .thus it is
advisable to keep supp in the lower part of rectum. 50% -70% of drug
administered rectally, reported to go directly into general circulation.
2. Physicochemical factors of the
drug
a. Lipid water solubility of a drug (partition coefficient):
- The lipid water partition coefficient of a drug is important in selecting
the suppository base and in anticipating drug release from that base.
- lipophilic distributed in a fatty suppository base has
tendencies to escape
drug fewerto the surrounding aqueous fluids.
- Thus water-soluble salts are preferred in fatty base suppository. water-
soluble base e.g: PEG, which dissolve in the rectal fluids, release both
water-soluble and oil-soluble drugs.
Drug solubility and suppository formulation
Solubility in Choice of
Fatbase Water
low high Fatty base
high low Aqueous base
low low Indeterminate
b. Degree of ionization:

The barrier separating colon lumen from the blood is preferentially

permeable to the unionized forms of drugs, thus absorption of drug
would be enhanced by increase the proportion of unionized drugs.

c. Concentration of a drug in a base:

- The more drugs in a base, the more drug will be available for
absorption.

- If the concentration of the drug in the intestinal lumen is above a

particular amount, the rate of absorption is not change by further
increase in concentration of drug.

- In general, the rate limiting step in drug absorption from suppository is

the partitioning of the dissolved drug from the melted base and not
the rate of solution of drug in the body fluid.
d. Particle size:
The smaller the particle size of undissolved drugs in a suppository, the
the dissolution of the particle and the greater the chance for
more
absorption.
rapid
3. Physiochemical Characteristics of the Base and
Adjuvant: a) Nature of the Base:
- Suppository base should be capable of melting, softening
or dissolving to
release the drug for absorption.
- Should not interact with the drug to inhibit its release as it may affect
absorption.
- If the base irritating the colon, it will promote colonic response, lead to
increase bowl movement and decrease absorption.
b) Presence of Adjuvant in Base :
Adjuvant in a formula may affect drug absorption, change the rheological
properties of the base at body temperature, or affected the dissolution of
the drug. E.g. surfactants
 Shapes and Sizes of
suppositories

0 For Children
1,2 & 3 For rectal use
4 Pessaries
A& B Nasal &
urethral
bougies
Classification Of
Suppositories
• Rectal suppositories
• Vaginal suppositories
(Pessaries)
• Urethral suppositories
(Bougies)
• Nasal suppositories
• Ear suppositories
 Characteristics of
suppositories
Rectal suppositories:

1. Rectal suppositories are usually about 32mm in length.

2. They are usually cylindrical and have one or both ends tapered.

3. Some rectal suppositories are a bullet, a torpedo or the little finger

like
shaped.

4. Adult rectal suppositories weigh about 2gm when coca butter is

used.

5. Children rectal suppositories weigh about 1gm and

have a corresponding reduction in size.

6. Intended for local action to relieve constipation, irritation, itching and

Vaginal suppositories:
1. They are also called Pessaries.
2. Usually globular, oviform and cone shaped.
3. There weigh about 3 – 5gm.
4. Intended for local effects like contraceptives, antiseptics in feminine
hygiene.
5. Used occasionally
Urethral suppositories:
1. Also called as Bougies. Occasionally used.
2. Usually, bougies are slender and pencil shaped.
3. Male urethral suppositories may be 3 – 6mm in diameter
approximately
and 100 – 150mm long.
4. These suppositories weigh about 4gm.
5. Female urethral suppositories are usually 60 – 75mm in length and
weighing about 2gm.
6. Intended for anti-bacterial or as a local anesthetic
preparative for urethral examination.
Suppository
base
The vehicle used in a suppository, via which drugs reach to the site
of action to exert it’s therapeutic effect is termed as suppository
base. The composition of suppository base plays an important
role in both the rate and extent of release of medications.
Suppository bases may be classified according to their composition
and physical properties:
1.Oleaginous (fatty) bases
Ex. Cocoabutter (Theobroma)
2.Water soluble or miscible bases
Ex. Glycero-Gelatin base/PEG
Properties of an ideal suppository
base
 Nontoxic and nonirritating to sensitive and inflamed tissues.
 Non sensitizing (allergic).
 Inert and compatible with a broad variety of medicaments.
 Can be easily manufactured by compression or molding.
 It has no meta-stable forms.
Dissolve or disintegrate in the presence of mucous secretions or
melt at body temperature (36 - 370 C) to allow for the release of
the medication.
Remain molten for a sufficient period of time to allow pouring
into moulds.
Solidify sufficiently rapidly to minimize sedimentation of
dispersed solids.
Shrink on cooling to allow easy withdrawal of the
suppository from the mold.
 Stable on storage, does not change color, odor and drug
release
pattern.
1. Oleaginous
bases
• Triglycerides obtained from the hydrogenation of vegetable oil,
such as, coconut oil, theobroma oil.

• Crude fats which are mixture of saturated & unsaturated

triglyceride, free fatty acids.

• If it be vegetable or animal fat, it’s acid value should be less

than 0.2, Iodine value less than 7 and Saponification value
between 200-245.

• The difference between melting & solidification points should

be small.
Advantages:
- They remain solid at Room Temp
- They melt readily at body temperature
- Other advantages of suppository bases
Drawbacks:
- Strong tendency to form isomerization which melts at lower
temperature (most serious).
- They rancidify & melt at warm weather
- They leak from body cavities.
Examples of oleaginous bases:
- Theobroma Oil ( Cocoa butter)
- Glycerin Bases
- synthetic fats
Cocoa butter
(Theobroma
oil)
 Cocoa butter is fat obtained from the
roasted seed of Theobroma cocoa.
 At room temperature it is a yellowish,
white solid having a faint, agreeable
chocolate like odour.
 Chemically, it is a triglyceride
(combination of glycerin and one or
different fatty acids) primarily of
oleopalmitostearin and oleodistearine.
 It melts at 30 - 350 C.
 It can exist in more than one crystalline
form
or exhibits polymorphism.
Advantages

 Melts just below the body temperature.

 Maintains its solidity at usual room temperatures.
 Readily liquefy on heating and solidify on cooling.
 Has good emollient properties useful for relieving inflammation.
 Shows good release of water soluble drugs
 Is not irritating to the mucous membrane.

Disadvantages
 Susceptible to rancidification, so it should be stored in dry place away
from light.
 It gives soft suppository when formulated along with lower melting
point actives including chloral hydrate, phenol and volatile oil.
 The physical property of the base varies from batch to batch.
 It requires extra lubricant during pouring in holder.
 Some times leakage may occur.
2. Hydrophilic suppositories base (Water soluble
or miscible base)
Water miscible bases are dissolved & disintegrated in the surface fluid &
releases the drug.
• Advantages:
1.Do not hydrolyze or deteriorate
2. Physiologically inert
3.Do not support mold growth
• Disadvantages:
- Crystal growth of certain medicament may occur
- Incompatible with bismuth salt, tannin& phenol.
• Example:
- PEG-1000, 4000 (Poly Ethylene Glycol)
- Glycerinated gelatin
 Glycerinated gelatin suppositories
 Prepared by dissolving granular gelatin (20%) in glycerin (70%) and
adding water or a solution or suspension of the medication (10%).
 Most frequently used in the preparation of vaginal suppositories,
requiring prolonged local action of the drug.
 This base softens and mixes with the physiologic fluids slower than
cocoa
butter and therefore provides a slower release.
 They tend to absorb moisture as a result of the hygroscopic nature of
glycerin and must be protected from atmospheric moisture.
 They have a dehydrating effect and irritate the tissues upon insertion.
However, adding water to the suppositories or moistening them prior to
insertion may reduce this effect.
 Likelihood of microbial contamination.
 Polyethylene glycol base (Macrogol)

 Polymers of ethylene oxide and water prepared to various chain

lengths, molecular weights, and physical states.
increases
Hardness with an increase in the molecular weight.
Various combinations of these PEGs may be prepared to achieve
a suppository base of the desired consistency and
characteristics.
They do not melt at body temperature but rather dissolve slowly
in the body’s fluids.
Suppositories made from these mixtures have melting points
considerably higher than body temperature to permit a slower
release of the medication from the base , and permits
convenient storage of these suppositories without need for
refrigeration.
Polyethylene glycol suppositories that do not contain at least
20% water should be dipped in water just before use to avoid
irritation of the mucous membranes after insertion.
 Miscellaneous Bases

Mixtures of oleaginous and water-soluble or water- miscible

materials.

Some are preformed emulsions, generally of the water-in-oil

type, or they may be capable of dispersing in aqueous fluids.
Example is polyoxyl 40 stearate, a surface-active agent that is
employed in a number of commercial suppository bases.

Mixtures of many fatty bases (including cocoa butter) with

emulsifying agents capable of forming water-in-oil emulsions
have been prepared.
Preparation of
suppositories
Suppositories are prepared by three methods:

(a) Hand rolling and shaping

(b) Compression

(c) Molding from a melt/Fusion

The method most frequently employed both on a small

scale
and on an industrial scale is molding.
Hand rolling and
shaping
 It is the oldest and simplest method of suppository preparation

 may be used when only a few suppositories are to be prepared

in a cocoabutter base.
 No need to heat the cocoa butter.

 A plastic-like mass is prepared by triturating grated (pulverized)

cocoa
butter and active ingredients in a mortar.
 The mass is formed into a ball in the palm of the hands, then
rolled into a uniform cylinder with a large spatula.
 The cylinder is then cut into the appropriate numberof pieces
which
are rolled on one end to produce a conical shape.
 The drug is Incorporated
into suppository By trituration or
made into fine kneading
powder base

Desired shape Rods are cut Mass is rolled

is given by into pieces into rod
hand shape by
fingers 63
2.
Compression
•Compression molding is a methodof preparing suppositories froma
mixture of mass grated suppository base and medicaments which is
forced into a special compression moldusing suppository making
machines.
• The suppository base and the other ingredients are combined by
thorough mixing.
• the friction of the process causing the base to soften into a past-
like
consistency.
• On large scale, mechanically operated and a warmed mixing
vessels are used.
• In the compression machine, the suppository mass is placed into a
cylinder which is then closed.
•Pressure is applied fromone end to release the mass fromthe other
end into the suppository mold or die.
Compression molding
machine
• Prepared mass C is placed in a cylinder A
•It is forced through a narrow opening D by means of
piston B into a mould.
•Threads of mass pass into the mould G and are
compressed until a homogenous fused mass is formed
in E.
•The mass and the compression cylinder of the machine
may be chilled to prevent heat of compression from
making the mass too fluid.
• When the die is filled with the mass, a movable end
'plate-F'at the back of the die is removed.
• Additional pressure is applied to eject the suppository.
 3. Fusion
molding
Fusion Molding involves:
• Melting the suppository base
• Dispersing or dissolving the drug in the melted base.
•The mixture is removed from the heat and
poured into a suppository mold.
• Allowing the melt to congeal
• Removing the formed suppositories from the
mold.
• The fusion method can be used with all types
of suppositories.
Suppository
Molds
 Molds in common use today
are made from stainless steel,
aluminum, brass, or plastic.

 Small scale molds are capable

of producing 6 or 12
suppositories in a single
operation.

 Industrial molds produce

hundreds of suppositories from
a single molding.
Lubrication of
molds
• Depending on the formulation, suppository molds may require
lubrication (eg. talc) before the melt is poured to facilitate clean
and easy removal of the molded suppositories.
• Lubrication is seldom necessary when the base is cocoa butter
or polyethylene glycol.
• Lubrication is usually necessary with glycerinated gelatin.

• A thin coating of mineral oil, glycerine or alcohol applied with

the
finger to the molding surfaces usually suffices.
• For synthetic bases or emulsifying bases lubrication is not
required.
Evaluation of suppositories

Finished suppositories are routinely inspected

for-
• appearance
• content uniformity
• Melting range test/micromelting range
• Softening time
• Drug release test
• Breaking test (Fragility test)
• Disintegration test
Packaging of
suppositories
• They should not touch each other, otherwise they may fuse together
Materials:
•Proper wrapping with aluminium foil, or paper is required --these are called
disposable molds.
Methods:
• Machine packaging avoid nonuniformity
-after solidification wrapping
-sealing using two halves of plastic
• In package moulding

-Top of package mould remain open, after mass is inserted, it is sealed

-High production rate
-At high temperature shape is retained