SALMAN BIN ABDULAZIZ UNIVERSITY

COLLEGE OF PHARMACY

Dr. Mohammad Khalid Anwer e-mail:- mkanwer2002@yahoo.co.in

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.