Transcript suppositories

SUPPOSITORIES
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Dose character:
 For rectal administration, one half to two or more
times than the oral dose is given.
- The correct dose of any drug depends on the
rate of release from the suppository
- Since the vehicle can change the rate of drug
absorption , the amount of drug to be given in
suppository dose depend on the vehicle, the
chemical and physical from the drug.
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Types:
 1- Rectal suppository: 32 mm in length, cylindrical, have
one or both end tapered.
a) Adult rectal supp. Weight 2gm
b) infant rectal supp.1gm
 2- Vaginal suppository: pessaries, 5gm, usually oviform
or cone shaped, weight from 3-5 gm
 3- Urethral suppository: bougies 4gm and 10-15 cm long
for male and 6-7.5cm long for female. , pencil shaped.
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Therapeutic uses
 Suppository can be used for local or systemic effect.
 The action depends on nature of drug , concentration
and rate of absorption
 Rectal suppository are intended for treatment of
constipation and hemorrhoids.
Suppositories are also administered for systemic action
(analgesics, antispasmodics, sedatives & tranquilizers).
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Factor affecting drug absorption form
rectal suppository:
1) Physiologic Factor:
The human rectum is approximately
15-20 cm in the length, when empty
of fecal material; it contains 2-3 ml of inert mucous
fluid. In resting state, the rectum is non motile.
There is no villa or microvillus on rectal mucosa.
Physiological factors include:
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A) 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.
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B) Circulation:
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.
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C) pH and lack of buffering capacity of the
rectal fluid :
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.
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2) Physiochemical characteristics 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 drug, in other word, distributed in a
fatty suppository base has fewer tendencies to
escape to the surrounding queues fluids
- .
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- Thus water-soluble salt 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.
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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
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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.
-
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- Scientists showed that: the rate, at which the
drug diffuses to the surface of the suppository,
Particle size, and presence of surface-active
agents are factors that affect drug release from
suppositories.
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3) Physiochemical Characteristics of
the Base and Adjuvant:
1)- Nature of the Base:
- Suppository base capable of melting,
softening or dissolving to release the drug
for absorption.
- If the base irritating the colon, it will
promote colonic response, lead to
increase bowl movement and decrease
absorption.
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2) 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.
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Specifications for Suppository
Bases :
1- Origin & Chemical Composition:
A brief description of the composition of the
base reveals the sours of the origin
(natural or synthetic or modified natural
products). Physical or chemical incompatibilities with other constituents may
be predicted if the exact formula
composition is known including
preservatives, antioxidants and emulsifiers
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2- Melting Range :
Suppository bases don't have a sharp melting
point, their melting characteristics are expressed
as ranges, indicating the temperature at which
the fats start to melt and the temperature at
which completely melted. Melting range is
usually determination by " Wiley melting point",
"Capillary melting point", " Incipient melting (or
thaw)point".
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3- Solid-Fat Index (SFI):
One can determine the solidification and
melting ranges of fatty bases as well as
the molding character, surface feel and
hardness of the bases. A base with sharp
drop in solids over a short temperature
span proves brittle if molded too quickly.
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The solid content at room temperature
could determine suppository hardness.
Since skin temperature is about 32° C,
one can predict that would be dry to touch
from a solid content over 30% at that
temperature.
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4- Solidification Point:
This test allow to determine the time required for
solidifying the base, when it is chilled in the mold
if the interval between the melting point and
solidifying point is 10° C or more, time required
for solidification may have to be shortened for
amore efficient manufacturing procedure by
refrigeration, if melting point 33° C and
solidifying point 20° C then it will be liquid for 13°
C, then the drug will sediment and the apex of
the suppository will contain all the drug.
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5- Hydroxyl Value:
"It is the number of milligrams.of KOH (Potassium
hydroxide) that would neutralize the acetic acid
used to acetylate 1g of fat. It reflects the monoand di-glyceride content of a fatty base.
6- Saponification Value:
The number of milligrams of KOH (Potassium
hydroxide) required to neutralize the free fatty
acids and saponify the ester contained in 1 g of
a fat. From saponification value we can know
the type of glyceride present (mono-, di- or tri-)
and also amount present.
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7- Iodine Value:
It is the number of grams of Iodine that reacts with l00 g of fat or other
unsaturated material.
The possibility of decomposition by moisture, acids, oxygen (which
leads to rancidity of fats) increases with higher iodine value.
8- Water Number:
It is the amount of water in grams that can be incorporated in l00g of
fat. The "water number" can be increased by the addition of surfaceactive agents.
9- Acid Value:
It is the number of milligrams of KOH (Potassium hydroxide) required
neutralizing the free fatty acids in I g substance (fat). Low acid value
or absence of acid value is important for good suppository bases.
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Properties of an Ideal Suppository
Base:
The ideal suppository base may be described as follows :
1- Melts at rectal temperature 36° C, or dissolve in rectal
fluid
2- Completely non toxic, and non irritating to sensitive and
inflamed tissues.
3- Compatible with a broad variety of drugs.
4-No metastable forms.
5- Shrinks sufficiently on cooling to be released form the
mold without the need for mold lubricants.
6- Non- sensitizing
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7- Has a melting and emulsifying property.
8- Water number is high (a high percentage of
water can incorporated in it)
9- It is stable on storage, dose not change odor,
color, release pattern.
10- Can be manufactured by molding either by
hand, compression, machine .
11- Acid value is below 0.2, saponification value
ranges from 200 to 245, and Iodine value is less
than 7.
12- SFI curve is sharp, in other word, the interval
between melting point and solidification point is
small
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Type of Suppository Bases:
A- Fatty Bases.
B- Hydrophilic Suppository Bases
C-water dispersible Bases
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A- Fatty Bases:
Cacao Butter (theobroma oil)
It is the most widely used suppository base. It satisfy many
requirement for ideal suppository base :
1) Bland.
2) Non reactive.
3) Melt at body
temperature.
- Cacao Butter is a triglyceride, yellowish white, solid, brittle
fat, smells and taste like chocolate. Its melting point
between 30-35° C, it iodine value is “between” 34-38 and
its acid value is no higher than 4, because cacao butter
can melt and rancid. So it must be stored in cool dry
place protected from light.
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Cacao butter exhibited polymorphism (exist
in different crystalline forms). Cacao butter
is thought to exist in 4 crystalline states:
1) α - crystal ‫ ــ‬melt at 22oC ‫ ــ‬unstable
2) γ - crystal ‫ ــ‬melt at 18oC ‫ ــ‬unstable
3) β’ - crystal ‫ ــ‬melt at 27oC ‫ ــ‬unstable
4) β – stable crystal ‫ ــ‬melt at 34-36oC ‫ــ‬
stable
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Various forms of cacao butter depend on:
1- Degree of heating.
2- Cooling process.
3- Conditions during this process.
The re-conversion to the stable B- form
takes form one to four days depending on
the storage temperature, the higher the
temperature the faster the change.
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Disadvantages of Cacao Butter
1- Rancidity and slow deterioration during storage.
2- Melt in warm weather.
3- Liquefy when incorporated with certain drug such as:
volatile oils, creosote, phenol and chloral hydrate.
4- Over heating lead to isomerizes to metastable form. So
this will decrease melting point.
5- Low contractility during solidification, suppository will
adhere to the mold and will be necessitates uses of
lubricant.
6- Quality of cacao butter varies with origin and treatment.
7- Water number is low (20-30), this could be improved by
addition of 5-10%tween61.
8- Leakage from the body.
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Advantages of Cacao Butter:
1- Non reactive.
2- Melt at body temp.
3- Solidification point lies 12-13° C below
melting point, during formulation the mass
can be stirring and maintain cacao butter
liquid below its solidification point.
4- Emulsion can be added in Conc 5-10 %
to keep insoluble drug suspended.
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5-Increase conc. of water soluble drugs, lead
to decrease melting point until eutectic
point is obtained
6- Melted cocoa butter is viscous (semisolid)
which help in corporation of drug. The
difference in melting point &solidification
point is large to give chance for
incorporation with drugs.
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B- Hydrophilic Suppository Bases:
1-Glycerine Suppositories:
Glycerine
91 g
Sod. Stearate
4g
Purified water
5g
To make approximately
l00g
2- Glycerated gelatin suppositories:
Drug & purified water
10g
Gelatin
20g
Glycerin
70g
- Because glycerin is hygroscopic, there suppositories are packed in
materials that protect them from environmental moisture.
- This base do not melt at body temp., but dissolve in the secretions of
the body cavity in which they are inserted.
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3-Polyethylen glycol (PEG):
Marketed as carbowax or polyethylenglycol, exist as liquid
or wax like solid depending on molecular weight. Their
water soluble, hygroscopic and vapor pressure decrease
with increasing average molecular weights. The wide
range of melting point and solubility makes possible the
formulation of suppository with various degrees of heat
stability and with different dissolution rates. They do not
hydrolyze or deteriorate, are physiologically inert and do
not support mold growth. Base usually dipped in water
before insertion, so that possible irritation maybe
eliminated
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3-WATER - DISPERSIBLE BASE
Several non-ionic surface active materials, closely related chemically to
PEG as suppository bases. The bases can be used for formulation
both water-soluble and oil-soluble drugs (e.g.; Tween & Span).
These surface active agents may be used alone, blended or used in
combination with other suppository vehicle. Another type of water
dispersible suppository vehicle is based on the use of water soluble
cellulose derivatives (e.g. methylcellulose & sodium
carboxymethylcellulose ).
Advantages of Water Dispersible Bases:
1. Stable on storage at elevated temperature.
2. Compatible with many drugs.
3. Non support of microbial growth, non toxic and non sensitive.
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Method Of Manufacture Of
Suppositories:
1- Hand Molding:
It is the oldest and simplest method, by rolling the
suppository into the desired shape. The mass is then
rolled into a cylindrical rod of desire length and diameter.
2- Compression Molding:
Elegant suppository can be made b compression the coldgrated mass into the desired shape .
It is simple and more elegant appearance than hand
molding.
It avoids the possibility of sedimentation of the insoluble
solids in the suppository base.
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3- Pour Molding:
Most commonly used method for production of
suppository on both small & large scale.
First, the base is melted on water bath, and then
the drugs are either emulsified or suspended in
it. Then, the mass is pour into cooled metal
molds, which are usually chrome or nickel
plated.
4- Automatic Molding Machine:
The molding operation (pouring, cooling &
removal) can be performed by machine .
The output of a typical rotary machine, range from
3500 to 6000 suppositories per hour.
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SPECIFIC PROBLEMS IN FORMULATING
SUPPOSITORIES :
1- Water in suppositories:
Use of water as a solvent for drug should be avoided for the
following
Reasons:
a- Water accelerates oxidation of fats.
b- If water evaporates, the dissolved substance crystallizes out.
c- Unless H2O is present at level than that requires for dissolving the
drug, the water has little value in facilitating drug absorption.
Absorption from water containing suppository enhance only if an oil
in water emulsion exist with more than 50% of the water in the
external phase .
d- Reaction between ingredients (in suppository) are more likely to
occur in the presence of water.
e- The incorporation of water or other substances that might be
contaminate with bacteria or fungi necessitates the addition of
bacteriostatic agents (as parabens)
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2- Hygroscopicity:
a- Glycerinated gelatin suppositories lost
moisture by evaporation in dry climates
and absorbed moisture under conditions of
high humidity
b- PEG bases are also hygroscopic.
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3- Incompatibilities:
a- PEG bases are incompatible with silver salt,
tannic acid, aminopyrine , quinine , icthammol,
asprine , benzoc.aine & sulphonamides .
b- Many chemicals have a tendency to crystallize
out of PEG, e.g.: sodium sarbital, salicylic acid &
camphor.
c- Higher concentration of salicylic acid softens
PEG to an ointment-like consistency, d- Aspirin
complexes with PEG.
e- Penicillin G , although stable in cocoa butter and
other fatty bases , was found to decompose in
PEG bases .
f- Fatty bases with significant hydroxyl values may
react with acidic ingredients.
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4- Viscosity:
The viscosity of the melted suppository base is important in the
manufacture of the suppository and to its behavior in the rectum
after melting.
Melted cocoa butter have low viscosity than glycerinated gelatin and
PEG type base in low viscosity bases, extra
Care must be exercised to avoid sedimentation of suspended particles.
To overcome the problems caused by use of low viscosity bases:
a- Use base with a more narrow melting rang that is closer to body
temperature.
b- The inclusion of approximately 2% aluminum monostearate not only
increase the viscosity of the fat base but to maintain homogenous
suspension of insoluble material.
c- Cetyl , stearyl or myristyl alcohols or stearic acid are added to
improve the consistency of suppositories .
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5- Brittleness :
Suppositories made from cocoa butter are elastic
and don't fracture readily.
Synthetic fat base with high degree of
hydrogenation and high stearate content and a
higher solids content at room temperature are
usually more brittle.
To overcome, 1) the temperature difference
between the melted base & the mold should be
minimal.
2) Addition of small amount of
Tween 80, castor oil, glycerin imparts plasticity
to a fat
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6- Volume contraction:
Occurs in many melted suppository base after cooling the
mold, result in:
a- Good mold release (contraction facilitate the removal of
the suppository from the mold , eliminating the need for
mold release agents).
b- Contraction hole formation at the open end of the mold,
this will lowered suppository . The contraction can be
eliminated by pouring a mass slightly above its
congealing temperature into a mold warmed at about the
same temperature or the mold is overfilled so that the
excess mass containing the contraction hole can be
scraped off.
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Lubricant or mold releasing agent:
Cocoa butter adhere to suppository molds
because of its low volume contraction. A various
mold lubricants or release agents must be used
to overcome this difficulty (mineral oil , aqueous
solution of sodium lauryl sulfate , alcohol ,
silicones , soap). The release of suppository
from damaged mold was improved by coating
the cavities with polytetrofluoroethylene
(Teflone).
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7- Rancidity and Antioxidant:
Rancidity results from the autoxidation and
subsequent decomposition of unsaturated
fats into low & medium molecular weight
saturated & unsaturated aldehydes ,
ketones and acids , which have strong
unpleasant odor. Example of effective
antioxidant are phenols such as "
hydroquinone or B-naphtholquinone.
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DOSAGE REPLACEMENT FACTOR
The amount of base that is replaced by
active ingredient in suppository formulation
can be calculated. The replacement factor
(f) is derived from the following equation:
F=100(E-G)+1
Where:
E= weight of pure suppository base.
G= weigh of suppositories with x% active
ingredient.
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WEIGHT AND VOLUME CONTROLE:
The amount of active ingredient in each suppository
depends on:
1 . Its concentration in the mass.
2. The volume of the mold cavity.
3. The specific gravity of the base.
4. The volume variation between molds (within 2% of the
desired value).
5. Weight variations between suppositories due to
inconsistencies in the manufacturing process. e.g.
incomplete closing of molds, uneven scrapings
(variations in weight should be within ± 5%)
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Quality Control of Suppository
1) Surface appearance and shape:
to evaluate: absence of fissuring – absence
of migration of active ingredient, absence
of pitting, absence of fat blooming
(dullness of surface)
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2) MELTING RANGE TEST:
Macromelting range: measures the time it takes for the
entire suppository to melt when immersed in a constant
temperature (370C) water bath.
Micromelting range: is the melting range measured in
capillary tubes for the fat base only.
The apparatus used for measuring the melting range of the
entire suppository is a USP tablet disintegration
apparatus. The suppository is completely immersed in
the constant temperature water bath, and the time for the
entire suppository to melt or dispense in the surrounding
water is measured. The in-vitro drug release pattern is
measured by using the same melting range apparatus.
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3) LIQUIFACTION OR SOFTENING TIME
TESTS OF RECTAL SUPPOSITORIES:
The "softening test" measures the
liquefaction time of rectal suppositories are
an apparatus that simulate
in-vitro conditions (at 37oC).
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4) BREAKING TEST:
It is designed as a method for measuring the
fragility or brittleness of suppositories.
The apparatus consists of double-wall chamber in
which the test suppository is placed. Water at
37C is pumped
through the double walls of the chamber, and the
suppository, contained in the drug inner
chamber,
supports a disk to which a rod is attached. The
outer end of the rod consists of another disc
to which weights are applied.
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 5) Mechanical strength: It is a force necessary to
break a supp. And indicate whether supp is
brittle or elastic. ( not less than 1.8-2 Kg) by
Erweka method
 6) Melting & solidification
 Solidification can be determine by using
evacuated flask into which the melt is placed,
the temp of cooling is noted to determine the
solidification point.
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7) DISSOLUTION TESTING:
The patterned is measured by using the
same melting range apparatus. If the
volume of water surrounding the
suppository is known, then by measuring
aliquots of the water for drug content at
various intervals within the melting period.
A (time versus drug release) curve could
be established and can be plotted.
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PACKAGING OF SUPPOSITORY
Suppository must be placed in a container in such
a manner that they do not touch each other.
• Staining, breakage or deformation by melting
caused by adhesion can result from poorly
wrapped packaged suppository. Suppository is
foiled in tin or Al paper and plastic.
• Over wrapping is done by hand or machine.
Many suppositories are not individually,
wrapped. In such cases, they are placed into
cardboard boxes or plastic containers that have
been molded to provide compartment for 6 or 12
suppositories.
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IN- PACKAGE MOLDING:
A significant advance in suppository manufacturing was the
development of automated method for molding
suppository, directly in their wrapping materials. This is
currently accomplished with either plastic or Al-foil.
*ADVANTAGE OF INPACKAGE MOLDING:
1. high production rate.
2. no generation of scraping.
3. no bulk handling.
4. maintenance of strict temperature control
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STORAGE
Suppository should be protected from heat,
preferably stored in the refrigerator.
Glycerinated gelatin suppositories should
be protected from heat, moisture, and dry
air by packaging in well-sealed containers
and storing in a cool place.
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