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Transcript of SALMAN BIN ABDULAZIZ UNIVERSITY COLLEGE OF PHARMACY Dr. Mohammad Khalid Anwer e-mail:-...
SALMAN BIN ABDULAZIZ UNIVERSITY
COLLEGE OF PHARMACY
Dr. Mohammad Khalid Anwer e-mail:- [email protected]
A suppository is a medicated or non medicated solid A suppository is a medicated or non medicated solid
dosage form generally intended for use in the rectum, dosage form generally intended for use in the rectum,
vagina and urethra. vagina and urethra.
Drugs may be administered in suppository form for either Drugs may be administered in suppository form for either
local or systemic effects. Such action depends on the local or systemic effects. Such action depends on the
nature of the drug, its concentration, and the rate of nature of the drug, its concentration, and the rate of
absorption. absorption.
Emollients, astringents, antibacterial agents, steroids, Emollients, astringents, antibacterial agents, steroids,
and local and local
anesthetics are dispensed in suppositoryanesthetics are dispensed in suppository
for treating local conditions for treating local conditions
Analgesics, antispasmodics, sedatives,Analgesics, antispasmodics, sedatives,
tranquilizers, and antibacterial agentstranquilizers, and antibacterial agents
are dispensed in suppository for systemic actionare dispensed in suppository for systemic action
1.1.Rectal suppositoriesRectal suppositories are tapered are tapered to resemble a torpedo shape. to resemble a torpedo shape. weigh about 2 g for adults and 1 weigh about 2 g for adults and 1 g for Children. g for Children.
Types and shapes of suppositoriesTypes and shapes of suppositories
2.Vaginal suppositories2.Vaginal suppositories molded in the molded in the
globular or oviform shape, or globular or oviform shape, or
compressed compressed
on a tablet press into modified on a tablet press into modified
conical conical
shapes. weigh about 3 to 5 g. shapes. weigh about 3 to 5 g. 3.Urethral suppositories3.Urethral suppositories called bougies, called bougies, are are pencil shaped and pointed at one pencil shaped and pointed at one extremity.extremity. for males weigh about 4 g each and for males weigh about 4 g each and are are 100 to 150 mm long;100 to 150 mm long; for females, they are 2 g each and for females, they are 2 g each and usually usually 60 to 75 mm in length. 60 to 75 mm in length.
Factors Affecting Drug Absorption from Factors Affecting Drug Absorption from Rectal SuppositoriesRectal Suppositories
Physiologic FactorsPhysiologic Factors
Many drugs cannot be administered orally Many drugs cannot be administered orally Why?Why?
Affected by the digestive juicesAffected by the digestive juices
Their therapeutic activity is modified by the liver Their therapeutic activity is modified by the liver
enzymes after absorption from the small intestine.enzymes after absorption from the small intestine.
The lower hemorrhoidal veins surrounding the The lower hemorrhoidal veins surrounding the
colon colon
and rectum enter into the inferior vena cava and and rectum enter into the inferior vena cava and
thus thus
bypass the liver. bypass the liver.
More than (50 to 70%) of rectally administered drugs More than (50 to 70%) of rectally administered drugs
can be absorbed from the ano rectal area into the can be absorbed from the ano rectal area into the
general circulation and still retain therapeutic values. general circulation and still retain therapeutic values.
Why?Why?11 The upper hemorrhoidal vein The upper hemorrhoidal vein
does does
connect with the portal veins connect with the portal veins
leading leading
to the liver. to the liver.
The lymphatic circulation helps The lymphatic circulation helps
also also
in absorbing a rectally in absorbing a rectally
administered administered
drug and in diverting the drug and in diverting the
absorbed absorbed
drug from the liver.drug from the liver.
22 The pH of the rectal mucosa has a rate-The pH of the rectal mucosa has a rate-
controlling role in drug absorption. controlling role in drug absorption. The colon has a pH of ≈ 6.8, with no The colon has a pH of ≈ 6.8, with no
buffer buffer
capacity, thus the dissolving drugs capacity, thus the dissolving drugs
determine determine
the pH in the ano-rectal area.the pH in the ano-rectal area.
Colonic lumen is permeable to the unionized forms Colonic lumen is permeable to the unionized forms
of of
drugs. Thus, weaker acids and bases are more drugs. Thus, weaker acids and bases are more
readily readily
absorbed than the stronger, highly ionized ones. absorbed than the stronger, highly ionized ones.
Thus, Thus,
the absorption of a drug would be enhanced by a the absorption of a drug would be enhanced by a
change change
in the pH of the rectal mucosa that would increase in the pH of the rectal mucosa that would increase
the the
proportion of unionized drug. proportion of unionized drug.
So absorption of acidic drugs can be increased So absorption of acidic drugs can be increased
when when
the pH of the surrounding fluids was lowered. the pH of the surrounding fluids was lowered.
The absorption of salicylic acid rises from 12% at The absorption of salicylic acid rises from 12% at
a pH a pH
7 to 42% at pH 4. In contrast, with a basic drug 7 to 42% at pH 4. In contrast, with a basic drug
like like
quinine, which becomes quinine, which becomes more ionized at the lower pHmore ionized at the lower pH
values,values, the absorption is the absorption is
decreased decreased
from 20% at pH 7 to 9% at pH 4. from 20% at pH 7 to 9% at pH 4.
The diffusivity is influenced by:The diffusivity is influenced by:
The nature of the medicament, such as the The nature of the medicament, such as the
presence of presence of
surfactant or the water-lipoidal solubility of the surfactant or the water-lipoidal solubility of the
drugdrug
The physiologic state of the colon (the amount and The physiologic state of the colon (the amount and
chemical nature of the fluids and solids present).chemical nature of the fluids and solids present).
The state of the anorectal membrane. This The state of the anorectal membrane. This
membranous membranous
wall is covered with a relatively continuous mucous wall is covered with a relatively continuous mucous
blanket, which can act as a mechanical blanket, which can act as a mechanical
barrier for the free passage of drug throughbarrier for the free passage of drug through
the pore space where absorption occurs.the pore space where absorption occurs.
33 The diffusion of the drug to the site on The diffusion of the drug to the site on
the the
rectal mucosa at which absorption rectal mucosa at which absorption
occurs.occurs.
Physicochemical Characteristics o f the DrugPhysicochemical Characteristics o f the Drug
drug absorptionabsorption from the anorectal area
Drug in vehicle- Drug in colon fluids- Drug in vehicle- Drug in colon fluids- Absorption through the rectal mucosaAbsorption through the rectal mucosa
1.1.Release the drug from the suppository base.Release the drug from the suppository base.
2.2.Distribute by the surrounding fluids to sites of Distribute by the surrounding fluids to sites of
absorptionabsorption
3.3.Dissolve in the fluidsDissolve in the fluids
4.4.Contact of the drug with the lumen walls, and to a Contact of the drug with the lumen walls, and to a
large number of absorption sites. large number of absorption sites.
Physicochemical Characteristics of the BasePhysicochemical Characteristics of the Base
For Fatty Bases:For Fatty Bases:• The absorption rate is faster from fatty bases having The absorption rate is faster from fatty bases having
a lower melting range than from those with higher a lower melting range than from those with higher
melting rangesmelting ranges
• Since fatty bases may harden for several months Since fatty bases may harden for several months
after molding, this rise in melting range certainly after molding, this rise in melting range certainly
would affect absorptionwould affect absorption
For Polyethylene Glycol BasesFor Polyethylene Glycol Bases•The absorption rate increases along with hydroxyl The absorption rate increases along with hydroxyl
values.values.
The absorption rate is faster as the molecular mass of The absorption rate is faster as the molecular mass of
the polyethylene glycols (PEGs) used increased.the polyethylene glycols (PEGs) used increased.
1.1. Origin and Chemical Composition.Origin and Chemical Composition.
Either entirely natural, synthetic or modified natural Either entirely natural, synthetic or modified natural
products. products.
Physical or chemical incompatibilities of the base with Physical or chemical incompatibilities of the base with
the other constituents may be pre dicted if the exact the other constituents may be pre dicted if the exact
formula composition is known, including formula composition is known, including
preservatives, antioxidants and emulsifiers.preservatives, antioxidants and emulsifiers.
Specifications for suppository basesSpecifications for suppository bases
characteristics are expressed as a range indicating characteristics are expressed as a range indicating
the temperature at which the fat starts to melt and the temperature at which the fat starts to melt and
the temperature at which it is completely melted.the temperature at which it is completely melted.
2.2. Melting Range. Melting Range.
Since fatty suppository bases are complex Since fatty suppository bases are complex
mixtures of triglycerides and therefore do mixtures of triglycerides and therefore do
not have sharp melting points, their not have sharp melting points, their
meltingmelting
3.3. Solid-Fat Index (SFI). Solid-Fat Index (SFI).
A base with a sharp drop in solids over a short A base with a sharp drop in solids over a short
temperature span proves brittle if molded too quickly. temperature span proves brittle if molded too quickly.
This type of base requires a reduced differential This type of base requires a reduced differential
between mold temperature and mass temperature for between mold temperature and mass temperature for
trouble-free molding. Suppository hardness can be trouble-free molding. Suppository hardness can be
determined by the solids content at room determined by the solids content at room
temperature. Since skin temperature is about 32°C, temperature. Since skin temperature is about 32°C,
one can predict a product that would be dry to touch one can predict a product that would be dry to touch
from a solids content over 30% at that temperature.from a solids content over 30% at that temperature.
4.4. Hydroxyl Value. Hydroxyl Value.
This is a measure of This is a measure of
unesterified positions on unesterified positions on
glyceride molecules and glyceride molecules and
reflects the monoglyceride reflects the monoglyceride
and diglyceride content of a and diglyceride content of a
fatty base. The number fatty base. The number
represents the milligrams of represents the milligrams of
KOH that would neutralize KOH that would neutralize
the acetic acid used to the acetic acid used to
acetylate 1 g of fat.acetylate 1 g of fat.
5.5. Solidification Point. Solidification Point.
Is the time required for solidifying the base when it is Is the time required for solidifying the base when it is
chilled in the mold. If the interval between the melting chilled in the mold. If the interval between the melting
range and solidification point is 10°C or more, the range and solidification point is 10°C or more, the
time required for solidification may have to be time required for solidification may have to be
shortened by refrigeration to produce a more efficient shortened by refrigeration to produce a more efficient
manufacturing procedure.manufacturing procedure.
6. 6. Saponification Value.Saponification Value.
Is the number of milligrams of potassium hydroxide Is the number of milligrams of potassium hydroxide
required to neutralize the free acids and saponify the required to neutralize the free acids and saponify the
esters contained in 1 g of a fat is an indication of the esters contained in 1 g of a fat is an indication of the
type (mono-, di-, or tri-) glyceride, as well as the type (mono-, di-, or tri-) glyceride, as well as the
amount of glyceride present.amount of glyceride present.
7.7. Iodine Value. Iodine Value.
Is the number of grams of iodine thatIs the number of grams of iodine that
reacts with 100 g of fat or other unsaturated reacts with 100 g of fat or other unsaturated
material. The possibility of decomposition by material. The possibility of decomposition by
moisture, acids, and oxygen (which leads to rancidity moisture, acids, and oxygen (which leads to rancidity
in fats) increases with high iodine values.in fats) increases with high iodine values.
8. 8. Water Number.Water Number.
Is the amount of water, in grams, that can be Is the amount of water, in grams, that can be
incorporated in 100 g of fat. incorporated in 100 g of fat.
The "water number" can be increased by the addition The "water number" can be increased by the addition
of surface active agents, monoglycerides, and other of surface active agents, monoglycerides, and other
emulsifiers.emulsifiers.
9.9. Acid Value. Acid Value. Is the number of milligrams of potassium hydroxide Is the number of milligrams of potassium hydroxide
required to neutralize the free acid in 1 g of required to neutralize the free acid in 1 g of
substance. Low "acid values" or complete absence of substance. Low "acid values" or complete absence of
acid are important for good suppository bases. acid are important for good suppository bases.
Free acids complicate formulation work, because they Free acids complicate formulation work, because they
react with other ingredients and can also cause react with other ingredients and can also cause
irritation when in contact with mucous membranes.irritation when in contact with mucous membranes.
Types of Suppository BasesTypes of Suppository BasesThe Ideal Suppository Base for long shelf-life
1.1. Having reached equilibrium crystallinity.Having reached equilibrium crystallinity.
The majority of components melt at rectalThe majority of components melt at rectal
temperature 36°Ctemperature 36°C
Bases with higher melting ranges may be Bases with higher melting ranges may be
employed for: employed for:
eutectic mixtures, addition of oils, balsams, and eutectic mixtures, addition of oils, balsams, and
suppositories intended for use in tropical suppositories intended for use in tropical
climates. climates.
2.2. Completely nontoxic and nonirritating to sensitive Completely nontoxic and nonirritating to sensitive
and inflamed tissues. and inflamed tissues.
3.3. Compatible with a broad variety of drugs. Compatible with a broad variety of drugs.
4.4. Has no metastable forms. Has no metastable forms.
5.5. Shrinks sufficiently on cooling to release itself Shrinks sufficiently on cooling to release itself
from the mold without the need for mold from the mold without the need for mold
lubricants.lubricants.
6.6. Has wetting and emulsifying properties. Has wetting and emulsifying properties.
7.7. High water number. High water number.
i.e.i.e. a high percentage of water can be a high percentage of water can be
incorporated in it. incorporated in it.
8.8. Stable on storage. Stable on storage.
i.e.i.e. does not change color, odor, or drug release does not change color, odor, or drug release
pattern. pattern.
9.9. Can be manufactured by molding by either hand, Can be manufactured by molding by either hand,
machine, compression, or extrusion.machine, compression, or extrusion.
If the base is fatty, it has the following If the base is fatty, it has the following
additional requirements:additional requirements:
10.10. Acid value below 3 Acid value below 3
11.11. Saponification value ranges from 200 to 245 Saponification value ranges from 200 to 245
12.12. Iodine value less than 7 Iodine value less than 7
13.13. The interval between "melting point (34 The interval between "melting point (34ooC)" and C)" and
"solidification (32"solidification (32ooC) point" is smallC) point" is small
14.14. Low melting ranges (30- 34 Low melting ranges (30- 34ooC) for incorporating C) for incorporating
drugs drugs
that increases the melting range of the base.that increases the melting range of the base.
Ex. Silver nitrate or lead acetateEx. 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.
Cocoa Butter (Theobroma Oil)Cocoa Butter (Theobroma Oil)
Cocoa butter is a yellowish white, solid, brittle fat.Cocoa butter is a yellowish white, solid, brittle fat.
Smells and tastes like chocolate.Smells and tastes like chocolate.
Its melting point lies between 30°C and 35°C.Its melting point lies between 30°C and 35°C.
Its iodine value is between 34 and 38.Its iodine value is between 34 and 38.
Its acid value is no higher than 4.Its acid value is no higher than 4.
Oleogenous Suppository BasesOleogenous Suppository Bases
ADVANTAGES of CACAO BUTTER as SUPPOSITORY ADVANTAGES of CACAO BUTTER as SUPPOSITORY BASEBASE
The most widely used suppository baseThe most widely used suppository base
It satisfies many of the requirements for an ideal baseIt satisfies many of the requirements for an ideal base
Safe, non reactive and melts atSafe, non reactive and melts at
body temperature. body temperature.
Cocoa butter does not contain emulsifiers and Cocoa butter does not contain emulsifiers and
therefore does not take up large quantities oftherefore does not take up large quantities of
water (maximum 20 to 30 g of water to 100 g water (maximum 20 to 30 g of water to 100 g
of cocoa butter). of cocoa butter).
The addition of emulsifiers such as Tween 60 (5 to The addition of emulsifiers such as Tween 60 (5 to
10%) increases the water absorption considerably. 10%) increases the water absorption considerably.
Emulsifiers also help to keep insoluble substances Emulsifiers also help to keep insoluble substances
suspended in the fat. Suspension stability is further suspended in the fat. Suspension stability is further
obtained by the addition of materials (aluminum obtained by the addition of materials (aluminum
monostearate, silica) that give melted fats thixotropic monostearate, silica) that give melted fats thixotropic
properties. There is always the possibility that the properties. There is always the possibility that the
suppositories containing these additives will harden suppositories containing these additives will harden
on storage. Therefore, prolonged, careful stability on storage. Therefore, prolonged, careful stability
observations are recommended.observations are recommended.
DISADVANTAGES of CACAO BUTTER as SUPPOSITORY DISADVANTAGES of CACAO BUTTER as SUPPOSITORY BASEBASE
Drugs as volatile oils, creosote, phenol, and chloral Drugs as volatile oils, creosote, phenol, and chloral
hydrate lower the melting point of cocoa butter.hydrate lower the melting point of cocoa butter.
To correct this condition, wax and spermaceti are To correct this condition, wax and spermaceti are
commonly used. commonly used.
Low contractility during solidification causes the Low contractility during solidification causes the
suppositories to adhere to molds and necessitates the suppositories to adhere to molds and necessitates the
use of mold release agents or lubricants.use of mold release agents or lubricants.
Cacao butter exhibits different polymorphisms Cacao butter exhibits different polymorphisms
each each
has different melting pointshas different melting points
Each of the different forms of cocoa butter has Each of the different forms of cocoa butter has
different melting points, and different drug release different melting points, and different drug release
rates. rates.
When cocoa butter is heated above its melting When cocoa butter is heated above its melting
temperature (36°C) and chilled to its solidification temperature (36°C) and chilled to its solidification
point (below 15°C), immediately after returning to point (below 15°C), immediately after returning to
room temperature this cocoa butter has a melting room temperature this cocoa butter has a melting
point of about 24°C, approximately 12° below its point of about 24°C, approximately 12° below its
original state. original state.
Cocoa butter is primarily a triglyceride. Cocoa butter is primarily a triglyceride.
A phenomenon due to the high proportion A phenomenon due to the high proportion
of unsaturated triglycerides is that it of unsaturated triglycerides is that it
exhibits polymorphism (the property of exhibits polymorphism (the property of
existing in different crystalline forms). existing in different crystalline forms).
Cocoa butter is thought to be capable of Cocoa butter is thought to be capable of existing in four crystalline states:existing in four crystalline states:1.1.TheThe αα formform Obtained by suddenly cooling melted cocoa butter Obtained by suddenly cooling melted cocoa butter to 0°C.to 0°C. It melts at 24°CIt melts at 24°C 2.2. TheThe ββ form form Crystallizes out of the liquefied cocoa butter with Crystallizes out of the liquefied cocoa butter with stirring stirring at 18 to 23°C. at 18 to 23°C. Its melting between 28 and 31°C.Its melting between 28 and 31°C.
3.3. TheThe ββ’’ formform
Changes slowly into the stableChanges slowly into the stable ββ form which melts form which melts between 34 and 35°C. between 34 and 35°C. This change is accompanied by a volume This change is accompanied by a volume contraction.contraction.
4.4. TheThe γγ formform Melting at 18°CMelting at 18°C Obtained by pouring a cool (20°C) cocoa butter, Obtained by pouring a cool (20°C) cocoa butter, before it before it solidifies, into a container which is cooled at deep solidifies, into a container which is cooled at deep freeze freeze temperature.temperature.
The formation of various forms of cocoa butter The formation of various forms of cocoa butter
depends on: depends on:
The degree of heatingThe degree of heating
The cooling processThe cooling process
The conditions during this process.The conditions during this process.
At temperatures below 36°C, negligible amounts of At temperatures below 36°C, negligible amounts of
the the
unstable forms are obtainedunstable forms are obtained
But prolonged heat above that critical temperature But prolonged heat above that critical temperature
causes causes
the formation of the unstable crystals with resulting the formation of the unstable crystals with resulting
lowered melting points. Thus, prolonged heating in lowered melting points. Thus, prolonged heating in
the the
process of melting the fats must be avoidedprocess of melting the fats must be avoided
The reconversion to the stable 3 form takes one to The reconversion to the stable 3 form takes one to
four four
days, depending on the storage temperature, the days, depending on the storage temperature, the
higher the higher the
temperature, the faster the change.temperature, the faster the change.
The formation of the unstable forms can be The formation of the unstable forms can be
avoided by: avoided by:
1.1. If the mass is not completely melted, the remaining If the mass is not completely melted, the remaining
crystals prevent the formation of the unstable crystals prevent the formation of the unstable
form. form.
2.2. Small amounts of stable crystals added to the Small amounts of stable crystals added to the
melted melted
cocoa butter accelerate the change from the cocoa butter accelerate the change from the
unstable to unstable to
the stable form; this process is called “the stable form; this process is called “SeedingSeeding." ."
3.3. The solidified melt is tempered at temperatures The solidified melt is tempered at temperatures
between between
28 and 3228 and 32ooC for hours or days, causing a C for hours or days, causing a
comparatively comparatively
quick Change from the unstable to the stable form.quick Change from the unstable to the stable form.
Cocoa Butter SubstitutesCocoa Butter Substitutes
Cocoa butter substitutes maintain the desirable Cocoa butter substitutes maintain the desirable
properties of cocoa butter and eliminate the properties of cocoa butter and eliminate the
undesirable ones.undesirable ones.Treatment o f Vegetable Oils to Produce Suppository BasesTreatment o f Vegetable Oils to Produce Suppository Bases
Synthetic or natural oils as vegetable oils as coconut Synthetic or natural oils as vegetable oils as coconut
or palm kernel oil are modified by:or palm kernel oil are modified by:
Esterification, hydrogenation Esterification, hydrogenation andand fractionation fractionation at at
different melting ranges to obtain the desired different melting ranges to obtain the desired
product.product.
Hydrophilic Suppository Bases
Glycerin Suppositories Glycerinated gelatin suppositories do not melt at Glycerinated gelatin suppositories do not melt at
body temperature but dissolve in the secretions of the body temperature but dissolve in the secretions of the
body cavity in which they are inserted (vaginal or body cavity in which they are inserted (vaginal or
rectal).rectal).
Solution time is regulated by the proportion of Solution time is regulated by the proportion of
gelatin/glycerin/water used, the nature of the gelatin gelatin/glycerin/water used, the nature of the gelatin
used, and the chemical reaction of the drug with used, and the chemical reaction of the drug with
gelatin.gelatin.
Glycerinated gelatin suppositories support mold or Glycerinated gelatin suppositories support mold or
bacterial growth, thus, they are stored in a cool place bacterial growth, thus, they are stored in a cool place
and often contain agents that inhibit microbial growth.and often contain agents that inhibit microbial growth.
Because glycerin is hygroscopic, these suppositories Because glycerin is hygroscopic, these suppositories
are packaged in materials that protect them from are packaged in materials that protect them from
environmental moisture.environmental moisture.
The Polyethylene GlycolsThe Polyethylene Glycols (Carbowax and Polyglycols) (Carbowax and Polyglycols)
Long-chain polymers of ethylene oxide have the Long-chain polymers of ethylene oxide have the
general formulageneral formula HOCHHOCH22 (CH (CH22OCHOCH22))XX CH CH22OHOH
When their average molecular weight ranges from When their average molecular weight ranges from
200 to 200 to
600 they exist as liquids, and as wax-like solids 600 they exist as liquids, and as wax-like solids
when when
their molecular weights are above 1000. their molecular weights are above 1000.
Their water solubility, hygroscopicity, and vapor Their water solubility, hygroscopicity, and vapor
pressure pressure
decrease with increasing average molecular decrease with increasing average molecular
weights.weights.
The wide range of melting points and solubilities The wide range of melting points and solubilities
makes makes
possible to formulate suppositories with various possible to formulate suppositories with various
degrees degrees
of heat stability and different dissolution rates. of heat stability and different dissolution rates.
Several combinations of polyethylene glycols have Several combinations of polyethylene glycols have
been prepared for suppository bases having different been prepared for suppository bases having different
physical characteristicsphysical characteristics . .
Base 1Base 1
Polyethylene glycol 1000 96 Polyethylene glycol 1000 96 % %
Polyethylene glycol 4000 4 Polyethylene glycol 4000 4 %%
Base 2Base 2
Polyethylene glycol 1000 75 Polyethylene glycol 1000 75 % % Polyethylene glycol 4000 25 Polyethylene glycol 4000 25 %%
This base has low-melting and require refrigeration.This base has low-melting and require refrigeration.It is useful when rapid disintegration is desired.It is useful when rapid disintegration is desired.
More heat stable than Base 1 and stored at higher More heat stable than Base 1 and stored at higher temperatures.temperatures.
It is useful when a slow release of active ingredients It is useful when a slow release of active ingredients is desired.is desired.
Polyethylene glycol suppositories do not require a Polyethylene glycol suppositories do not require a
mold lubricant and are easier to prepare than cocoa mold lubricant and are easier to prepare than cocoa
butter suppositories.butter suppositories.
They are physiologically inert, do not hydrolyze or They are physiologically inert, do not hydrolyze or
deteriorate and do not support mold growth. deteriorate and do not support mold growth.
ADVANTAGES of POLYETHYLENE ADVANTAGES of POLYETHYLENE GLYCOL GLYCOL
as SUPPOSITORY BASEas SUPPOSITORY BASE
Most patients do feel discomfort from the use of Most patients do feel discomfort from the use of
these suppositories, because this type of Bases cause these suppositories, because this type of Bases cause
irritation "irritation "stingsting“ to mucous membranes when water “ to mucous membranes when water
drawn from the mucosa. This irritation may be drawn from the mucosa. This irritation may be
eliminated by dipping in water before insertion or by eliminated by dipping in water before insertion or by
addition of 10% water to facilitate solution of the addition of 10% water to facilitate solution of the
suppository after insertion.suppository after insertion.
DISADVANTAGES of POLYETHYLENE DISADVANTAGES of POLYETHYLENE GLYCOLGLYCOL
as SUPPOSITORY BASEas SUPPOSITORY BASE
Water-Dispersible BasesWater-Dispersible Bases
The surfactants most commonly used in suppository The surfactants most commonly used in suppository
formulations are the polyoxyethylene sorbitan fatty formulations are the polyoxyethylene sorbitan fatty
acid estersacid esters ( (TweenTween), ), the polyoxyethylene stearatesthe polyoxyethylene stearates
((MyrjMyrj) ) and the sorbitan fatty acid estersand the sorbitan fatty acid esters ( (SpanSpan and and
ArlacelArlacel). ). These surface active agents may be used These surface active agents may be used
alone, blended, or used in combination with other alone, blended, or used in combination with other
suppository vehicle materials to yield a wide range suppository vehicle materials to yield a wide range
of melting points and consistencies.of melting points and consistencies.
These are nonionic surface active materials, related These are nonionic surface active materials, related
chemically to the polyethylene glycols.chemically to the polyethylene glycols.
Can be used for formulating both water-soluble Can be used for formulating both water-soluble
and oil-and oil-
soluble drugs. soluble drugs.
Can be stored and handed at elevated Can be stored and handed at elevated
temperaturestemperatures
Have broad drug compatibility.Have broad drug compatibility.
Nonsupport of microbial growth, nontoxic and not Nonsupport of microbial growth, nontoxic and not
cause cause
sensitivity.sensitivity.
ADVANTAGES of WATER-DISPERIBLE ADVANTAGES of WATER-DISPERIBLE BASES as SUPPOSITORY BASEBASES as SUPPOSITORY BASE
Caution must be taken in the use of surfactants Caution must be taken in the use of surfactants
with drugs with drugs
due to the increase in the rate of drug absorption. due to the increase in the rate of drug absorption.
These surface active agents can show interaction These surface active agents can show interaction
with with
drugs and a consequent decrease in therapeutic drugs and a consequent decrease in therapeutic
effects.effects.
DISADVANTAGES of WATER-DISADVANTAGES of WATER-
DISPERIBLE BASES as SUPPOSITORY DISPERIBLE BASES as SUPPOSITORY
BASEBASE
Compressed Tablet SuppositoriesCompressed Tablet Suppositories
Rectal suppositories usually are not compressed Rectal suppositories usually are not compressed
as tablets, because the amount of liquid in the as tablets, because the amount of liquid in the
rectal cavity is insufficient for tablet disintegration. rectal cavity is insufficient for tablet disintegration.
Effervescent tabletsEffervescent tablets aid disintegration, as carbon aid disintegration, as carbon
dioxide releasing laxative suppositories. dioxide releasing laxative suppositories.
This compressed rectal suppository is coated This compressed rectal suppository is coated
with water-soluble polyethylene glycol to aid with water-soluble polyethylene glycol to aid
in insertion into the rectum.in insertion into the rectum.
The compressed tablet for vaginal use weighing The compressed tablet for vaginal use weighing
about 3 g with almond shape to ease insertion. The about 3 g with almond shape to ease insertion. The
moisture level of the vagina is sufficient for moisture level of the vagina is sufficient for
disintegration and dissolution.disintegration and dissolution.
A typical vaginal tablet contains active ingredients, A typical vaginal tablet contains active ingredients,
with boric and/or phosphoric acid for adjusting the with boric and/or phosphoric acid for adjusting the
acidity of the vagina to pH 5. Vaginal suppositories acidity of the vagina to pH 5. Vaginal suppositories
are usually used for systemic or topical therapy, as are usually used for systemic or topical therapy, as
in the treatment of vaginitis, or as a spermatocide.in the treatment of vaginitis, or as a spermatocide.
Soft gelatin capsules filled with liquid or solid Soft gelatin capsules filled with liquid or solid
drugs used for vaginal use. drugs used for vaginal use.
The suppositories are non-melting,The suppositories are non-melting,
but dissolve in body fluids.but dissolve in body fluids.
Glycerinated gelatin suppositories are hygroscopic, Glycerinated gelatin suppositories are hygroscopic,
they lose moisture by evaporation in dry climates and they lose moisture by evaporation in dry climates and
absorb moisture under conditions of high humidity.absorb moisture under conditions of high humidity.
Polyethylene glycol bases are hygroscopic, the rate Polyethylene glycol bases are hygroscopic, the rate
of moisture change in polyethylene glycol bases of moisture change in polyethylene glycol bases
depends on humidity, temperature and on the chain depends on humidity, temperature and on the chain
length of the molecule. As the molecular weight length of the molecule. As the molecular weight
increases, the hygroscopicity decreases.increases, the hygroscopicity decreases.
Hygroscopicity
Formulation of SuppositoriesFormulation of Suppositories
Use of water as a solvent for incorporating Use of water as a solvent for incorporating
substances in suppository bases should be avoided substances in suppository bases should be avoided
for the following reasons.for the following reasons.
1.1. Water accelerates the oxidation of fats. Water accelerates the oxidation of fats.
2.2. If the water evaporates, the dissolved substances If the water evaporates, the dissolved substances
would crystallize out.would crystallize out.
3.3. Reactions between ingredients are more likely to Reactions between ingredients are more likely to
occur occur
in the presence of water. in the presence of water.
4.4. Bacterial or fungal growth necessitates the Bacterial or fungal growth necessitates the
addition of addition of
bacteriostatic agents as parabens.bacteriostatic agents as parabens.
Water in Suppositories
The viscosity of the melted suppository mass is The viscosity of the melted suppository mass is
important in the manufacture of the suppository and important in the manufacture of the suppository and
to its behavior in the rectum after melting. to its behavior in the rectum after melting.
Melted cocoa butter and some of its substitutes Melted cocoa butter and some of its substitutes
have low viscosities, whereas the glycerinated gelatin have low viscosities, whereas the glycerinated gelatin
and polyethylene glycol type base have viscosities and polyethylene glycol type base have viscosities
considerably higher than cocoa butter. considerably higher than cocoa butter.
Viscosity
In the manufacture of suppositories made with In the manufacture of suppositories made with
low-viscosity bases, extra care must be exercised to low-viscosity bases, extra care must be exercised to
avoid the sedimentation of suspended particles. Poor avoid the sedimentation of suspended particles. Poor
technique can lead to nonuniform suppositories, technique can lead to nonuniform suppositories,
particularly in the distribution of active ingredients. particularly in the distribution of active ingredients.
To prevent segregation of particles suspended in To prevent segregation of particles suspended in
molten bases, the well-mixed mass should be handled molten bases, the well-mixed mass should be handled
at the lowest temperature necessary to maintain at the lowest temperature necessary to maintain
fluidity, constantly stirred without entrapping air, and fluidity, constantly stirred without entrapping air, and
quickly solidified in the mold.quickly solidified in the mold.
The following approaches may be taken to overcome The following approaches may be taken to overcome
the the
problems caused by use of low viscosity bases.problems caused by use of low viscosity bases.
1.1. Use a base with a more narrow melting range that Use a base with a more narrow melting range that
is is
closer to body temperature.closer to body temperature.
2.2.The inclusion of approximately 2% aluminum The inclusion of approximately 2% aluminum
monostearate not only increases the viscosity of the monostearate not only increases the viscosity of the
fat base considerably, but also aids in maintaining a fat base considerably, but also aids in maintaining a
homogeneous suspension of insoluble materials. homogeneous suspension of insoluble materials.
Cetyl, stearyl, or myristyl alcohols or stearic acid are Cetyl, stearyl, or myristyl alcohols or stearic acid are
added to improve the consistency of suppositories.added to improve the consistency of suppositories.
Suppositories made from cocoa butter are elastic Suppositories made from cocoa butter are elastic
and do and do
not fracture. not fracture.
Synthetic fatty bases with a high degree of Synthetic fatty bases with a high degree of
hydrogenation hydrogenation
are more brittle. Fracturing of the suppository are more brittle. Fracturing of the suppository
made with made with
such bases is induced by rapid chilling (shock such bases is induced by rapid chilling (shock
cooling) of cooling) of
the melted bases in an extremely cold mold.the melted bases in an extremely cold mold.
Brittle suppositories have problems in Brittle suppositories have problems in
manufacturing, manufacturing,
handling and wrapping. handling and wrapping.
To overcome this difficulty, the temperature To overcome this difficulty, the temperature
differential between melted base and mold should be differential between melted base and mold should be
as small as possible. Addition of a small amount of as small as possible. Addition of a small amount of
Tween 80, Tween 85, fatty acid monoglycerides, Tween 80, Tween 85, fatty acid monoglycerides,
castor oil, glycerin, or propylene glycol increases its castor oil, glycerin, or propylene glycol increases its
plasticity and renders it less brittle.plasticity and renders it less brittle.
Brittleness
To calculate the amount of drug per suppository, To calculate the amount of drug per suppository,
the density of the base must be known. the density of the base must be known.
The volume of the mold cavity is fixed, and therefore, The volume of the mold cavity is fixed, and therefore,
the weight of the individual suppository depends on the weight of the individual suppository depends on
the density of the mass. the density of the mass.
Knowledge of the suppository weight can be Knowledge of the suppository weight can be
obtained from a given mold and density of the chosen obtained from a given mold and density of the chosen
base; the active ingredients can then be added to the base; the active ingredients can then be added to the
bulk base in such an amount that the exact quantity bulk base in such an amount that the exact quantity
of drug is present in each molded suppository. of drug is present in each molded suppository.
Density
If volume contraction occurs in the moldIf volume contraction occurs in the mold
during cooling, additional compensation during cooling, additional compensation
must be made to obtain the proper suppository must be made to obtain the proper suppository
weight. weight.
Thus, density alone cannot be the sole criterion for Thus, density alone cannot be the sole criterion for
calculating suppository weight per fixed volume mold. calculating suppository weight per fixed volume mold.
When volume contraction occurs, the suppository When volume contraction occurs, the suppository
weight is determined empirically by small batch runs.weight is determined empirically by small batch runs.
This phenomenon occurs in many meltedThis phenomenon occurs in many melted
suppository bases after cooling in the mold. suppository bases after cooling in the mold.
The results are manifested in the following two ways.The results are manifested in the following two ways.
1. Good mold release. This is caused by the mass 1. Good mold release. This is caused by the mass
pulling away from the sides of the mold. This pulling away from the sides of the mold. This
contraction facilitates the removal of the suppositories contraction facilitates the removal of the suppositories
from the mold, eliminating the need for mold release from the mold, eliminating the need for mold release
agents.agents.
Volume Contraction
2. Contraction hole formation at the 2. Contraction hole formation at the
open end of the mold. This open end of the mold. This
undesirable feature results in undesirable feature results in
lowered suppository weight and lowered suppository weight and
imperfect appearance of the imperfect appearance of the
suppository. suppository. The contraction can be eliminated by pouring a mass The contraction can be eliminated by pouring a mass
slightly above its congealing temperature into a slightly above its congealing temperature into a
mold warmed to about the same temperature. In mold warmed to about the same temperature. In
volume production using standard molds, where volume production using standard molds, where
adequate control of temperature may not be adequate control of temperature may not be
feasible, the mold is overfilled so that the excess feasible, the mold is overfilled so that the excess
mass containing the contraction hole can be scraped mass containing the contraction hole can be scraped
off.off.
Cocoa butter adheres to suppositoryCocoa butter adheres to suppository
molds because of its low volume contraction. molds because of its low volume contraction.
These suppositories are difficult to remove from the These suppositories are difficult to remove from the
molds, and various mold lubricants or release agents molds, and various mold lubricants or release agents
must be used to overcome this difficulty. must be used to overcome this difficulty.
Mineral oil, an aqueous solution of sodium lauryl Mineral oil, an aqueous solution of sodium lauryl
sulfate, various silicones, alcohol, and tincture of sulfate, various silicones, alcohol, and tincture of
green soap are examples of agents employed for this green soap are examples of agents employed for this
purpose. purpose.
They are applied by wiping, brushing, or spraying. They are applied by wiping, brushing, or spraying.
The release of suppositories from damaged molds The release of suppositories from damaged molds
was improved by coating the cavities with polytetra was improved by coating the cavities with polytetra
fluoroethylene (Teflon).fluoroethylene (Teflon).
Lubricants or Mold Release Agents
Confusion may take place between the acidity of Confusion may take place between the acidity of
fats with rancidity. fats with rancidity.
The presence of free fatty acids is no indication of The presence of free fatty acids is no indication of
rancidity or that such a product may become rancid.rancidity or that such a product may become rancid.
Rancidity results from the autoxidation and Rancidity results from the autoxidation and
decomposition of unsaturated fats into low and decomposition of unsaturated fats into low and
medium molecular weightmedium molecular weight
saturated and unsaturated aldehydes, ketones and saturated and unsaturated aldehydes, ketones and
acids, which have strong, unpleasant odors. acids, which have strong, unpleasant odors.
Rancidity and Antioxidants
The lower the content of unsaturated fatty acid The lower the content of unsaturated fatty acid
constituents in a suppository base, the greater is its constituents in a suppository base, the greater is its
resistance to rancidity. resistance to rancidity.
Since this reaction begins with the formation of Since this reaction begins with the formation of
hydroperoxides, the measure of autoxidation is the hydroperoxides, the measure of autoxidation is the
peroxide value (active oxygen) which is a measure peroxide value (active oxygen) which is a measure
of the iodine liberated from an acidified solution of of the iodine liberated from an acidified solution of
potassium iodide by "peroxide oxygen" of the fats.potassium iodide by "peroxide oxygen" of the fats.
Examples of effective antioxidants:Examples of effective antioxidants:
PhenolsPhenols: such as m- or p-diphenols; : such as m- or p-diphenols; αα-naphthol;-naphthol;
QuinonesQuinones: such as hydroquinone or : such as hydroquinone or ββ--
naphthoquinone;naphthoquinone;
TocopherolsTocopherols: particularly the : particularly the αα and and ββ forms; forms;
GossypolGossypol present in cottonseed oil; present in cottonseed oil;
SesamolSesamol present in sesame oil; present in sesame oil;
Propyl gallatePropyl gallate and and gallicgallic acid; acid;
TanninsTannins and tannic acid; and tannic acid;
Ascorbic acidAscorbic acid and its esters; and its esters;
ButylhydroxyanisoleButylhydroxyanisole (BHA) and butylhydroxytoluene (BHA) and butylhydroxytoluene
(BHT).(BHT).
An Approach in Formulating SuppositoriesAn Approach in Formulating SuppositoriesThe important considerations of the formulator are:The important considerations of the formulator are:
Is the medication intended for local or systemic use?Is the medication intended for local or systemic use?
Is the site of application rectal, vaginal or urethral?Is the site of application rectal, vaginal or urethral?
Is the desired effect to be quick or slow and prolonged?Is the desired effect to be quick or slow and prolonged?
Preliminary suppository bases to be studied are first Preliminary suppository bases to be studied are first
evaluated by measuring drug availability from the evaluated by measuring drug availability from the
suppository in water at 36 to 37°C.suppository in water at 36 to 37°C.
Availability and cost of the suppository basesAvailability and cost of the suppository bases
Stability of both active ingredients and base at 4°C Stability of both active ingredients and base at 4°C
and and
room temperature.room temperature.
Ease of molding and release in the manufacturing Ease of molding and release in the manufacturing
equipment.equipment.
Toxicity (irritancy) and drug availability are measured Toxicity (irritancy) and drug availability are measured
in in
animals before the medication is ready for human animals before the medication is ready for human
clinical trials.clinical trials.
Manufacture of Manufacture of SuppositoriesSuppositoriesManufacture of Manufacture of SuppositoriesSuppositories
Three methods are used in preparing Three methods are used in preparing
suppositories:suppositories:
Molding by handMolding by hand
Compression moldingCompression molding
Pour moldingPour molding
Compression MoldingCompression Molding
A more uniform and pharmaceutically elegant A more uniform and pharmaceutically elegant
suppository can be made by compressing the cold suppository can be made by compressing the cold
mass into a desired shape. mass into a desired shape.
A hand turned wheel pushes a piston against A hand turned wheel pushes a piston against
the the
suppository mass contained in a cylinder, so suppository mass contained in a cylinder, so
that the that the
mass is extruded into molds (usually three). mass is extruded into molds (usually three).
Pour MoldingPour MoldingThe most commonly used method for producingThe most commonly used method for producing
suppositories on both a small and a large scale. suppositories on both a small and a large scale.
First, the base material is melted, preferably on a water First, the base material is melted, preferably on a water
or or
steam bath to avoid local overheatingsteam bath to avoid local overheating
Then the active ingredients are either emulsified or Then the active ingredients are either emulsified or
suspended in it. suspended in it.
Finally, the mass is poured into cooled metal molds, Finally, the mass is poured into cooled metal molds,
which which
are usually chrome or nickel-plated. are usually chrome or nickel-plated.
Packaging of Molded SuppositoriesPackaging of Molded Suppositories
Suppositories must be packaged so that each Suppositories must be packaged so that each
suppository is overwrapped, or they must be placed suppository is overwrapped, or they must be placed
in a container in that they do not touch each other. in a container in that they do not touch each other.
Suppositories usually are foiled in tin,Suppositories usually are foiled in tin,
aluminum, paper and plastic strips. aluminum, paper and plastic strips.