SUPPOSITORIES
Syllabus:
Factors affecting drug absorption from rectal suppositories,
suppository bases, preparation of suppository, packing and storage.
Questions:
1. Define suppositories and displacement value. (98) [4]
2. Discuss different suppository bases. (98) [4]
3. Write in brief, the preparation , packaing and storage of
suppositories (98) [4]
4. Give the ideal properties of suppository bases.
5. Discuss the problems encountered in manufacturing of
suppositories such as hygroscopicity, incompatibilities, viscosity etc. (96)
[8]
6. Short note on packing of suppositories. (95) [4]
7. Short notes on suppository bases.
(93) [4]
8. Factors affecting drug absorption from rectal
suppositories. (93) [4]
DEFINITION
Definition:
·
Suppositories are specially shaped solid dosage
form of medicament for insertion into body cavities other than mouth.
·
They may be inserted into rectum, vagina or the
urethra.
·
These products are so formulated that after
insertion, they will either melt or dissolve in the cavity fluids to release
the medicament.
TYPES OF SUPPOSITORIES
1. Rectal suppositories: These are meant for introduction into the rectum for local and
systemic effect.
2. Pessaries: These are meant for
introduction into vagina for local action. These are larger than rectal
suppositories (3 – 6 gm).
3. Urethral bougies: These are meant for introduction into
urethra.
Weight: 2 – 4 gm Length:
2 – 5 inches.
4. Nasal bougies: These are meant for introduction
into nasal cavities.
Weight: 1gm Length:
9 – 10 cm
Advantages of rectal suppositories:
(i) Mechanical action: The rectal
suppositories are extensively used as a mechanical aid to bowel evacuation
which produce its action by either irritating the mucous membrane of the rectum
(e.g. glycerol and bisacodyl) or by lubricating action or by mechanical
lubrication.
(ii) Local action: The rectal suppositories
may be used for soothing, antiseptic, local anaesthetic action or for
astringent effect. Therefore, they may contain
soothing e.g.
zinc oxide
local anaesthetic- e.g. cinchocaine, benzocaine
astringents e.g. bismuth subgallate, hamamelis extract and
tannic acid
antiinflammatory e.g.
hydrocortisone and its acetate.
(iii) To provide systemic action:
Suppositories are convenient mode of administration of drugs which irritate the
gastrointestinal tract, cause vomiting, are destroyed by the hepatic
circulation, or are destroyed in the stomach by pH changes, enzymes etc.
Partial bypass: The lower portion of the rectum affords a large
absorption surface area from which the soluble substances can absorb and reach
the systemic circulation.
e.g. aminophylline used in asthmatic and chronic
bronchitis.
morphine a
powerful analgesic
ergotamine tartarate used to treat migraine
indomethacin and phenyl butazone analgesic and anti-inflammatory
actions.
Systemic treatment by the rectal
route is of particular value for
(a) treating
patients who are unconscious, mentally disturbed or unable to tolerate oral
medication because of vomiting or pathological conditions of the alimentary
tract.
(b) administering
drugs, such as aminophylline, that cause gastric irritation, and
(c) treating
infants.
PROPERTIES OF
IDEAL SUPPOSITORY BASE
1.
It should melt at rectal temperature (360)
or dissolve or disperse in body fluid. For eutectic mixtures and in tropical
climate the melting range of the base should be higher.
2.
Release medicaments easily.
3.
Shape should remain intact while handling.
4.
Non-toxic and non-irritant to sensitive and inflammed
mucous membrane.
5.
It should be stable on storage i.e. it does not change
color, odor, or drug release pattern.
6.
Compatible with broad variety of drug and adjuvants.
7.
It should shrink so that it comes out easily from the
mould without the use of any lubricants.
For
fatty bases the following additional specifications are required:
8.
“Acid value” is below 0.2
9.
“Saponification value” ranges from 200 to 245
10. “Iodine
value” is less than 7
11. The
interval point and solidification point is small.
SUPPOSITORY BASES
Classification of suppository bases
1.
Fatty bases –
they melt at body temperature.
2.
Water-soluble or
water miscible base – they dissolve or disperse in rectal secretions.
3.
Emulsifying bases
– they emulsifies small amount of aqueous solution of drug.
FATTY BASES
Example:
Theobroma oil (Cocoa butter), Synthetic fats.
Theobroma
oil (Cocoa butter)
·
It is a yellowish-white solid having chocolate
flavor.
·
It is a mixture of glyceryl esters of stearic,
palmitic, oleic and other fatty acids.
Advantages:
(a) A
melting point range of 30 to 36 0C; hence it is solid at normal room
temperatures but melts in the body.
(b) Ready
liquefaction on warming and rapid setting on cooling.
(c) Miscibility
with many ingredients.
(d) Blandness
i.e. does not produce irritation.
Disadvantages:
(a) Polymorphism
Cocoa butter has three polymorphs
a-crystals
(unstable, m.p. 200C), b-crystals (stable, m.p. 360C) and g-crystals
(unstable, 150C).
When melted and cooled it
solidifies in different crystalline forms, depending on the temperature of
melting, rate of cooling and size of the mass. If melted below 360C
and slowly cooled it forms stable b-crystals with normal melting point, but if over-heated
it may produce, on cooling, unstable g-crystals, which melt at
about 150C, or a-crystals, melting at about 200C. These
unstable forms eventually return to the stable condition but this may take
several days and meanwhile, the suppositories may not set at room temperature
or, if set by cooling, may remelt in the warmth of the patient’s home.
This lowering of the
solidification point can also lead to sedimentation of suspended solids.
Consequently, great care must be taken to avoid over-heating the base when
making theobroma oil suppositories.
(b) Adherence to mould
Because theobroma oil does not
contract enough on cooling to loosen the suppositories in the mould, sticking
may occur, particularly if the mould is worn. This is prevented by lubricating
the mould before use.
(c) Softening point too low
for hot climates
To raise the softening point,
whit beeswax may be added to theobroma oil suppositories intended for use in
tropical and subtropical countries.
(d) Melting point reduced by
soluble ingredients
Substances, such as chloral
hydrate, that dissolve in theobroma oil, may lower its melting point to such an
extent that the suppositories are too soft for use. To restore the melting
point, a controlled amount of white beeswax may be added.
(e) Slow deterioration during
storage
This is due to oxidation of the
unsaturated glycerides.
(f) Poor water absorbing
capacity
This fault can be improved by the
addition of emulsifying agents.
(g) Leakage from the body
Sometimes melted base escapes
from the rectum or vagina. This is most troublesome with pessaries because of
their larger size, and therefore, these are rarely made with theobroma oil.
(h) Relatively high cost
Synthetic fats
As a substitute of theobroma
oil a number of hydrogenated oils, e.g.
hydrogenated edible oil, arachis oil, coconut oil, palm kernel oil, stearic and
a mixture of oleic and stearic acids are recommended.
[N.B. Synthetic suppositories
bases are by hydrogenation and subsequent heat treatment of vegetable oils such
as palm oil and arachis oil. The oils are generally esters of unsaturated fatty
acids. Hydrogenation saturates the unsaturated fatty acids and heat treatment
splits some of the triglycerides into fatty acids and partial esters (mono- and
di-glycerides). ]
Advantages of these synthetic fats over theobroma oil:
1.
Their solidifying points are unaffected by overheating.
2.
They have good resistance to oxidation because their unsaturated
fatty acids have been reduced.
3.
Their emulsifying and water absorbing capacities are
good. [They usually
contain a proportion of partial glycerides some of which, e.g. glyceryl
monostearate, are w/o emulsifying agents and, therefore, their emulsifying and
water absorbing capacity are good.
4.
No mould lubricant is required because they contract significantly on
cooling.
5.
They produce colorless, odourless and elegant
suppositories.
Disadvantages:
1.
They should not be cooled in refrigerator because they
become brittle if cooled quickly. Certain additives e.g. 0.05 % polysorbate80, help to correct this
fault.
2.
They are more fluid than theobroma oil when melted and
at this stage sedimentation rate is greater. Thickeners such as magnesium stearate , bentonite
and colloidal silicon dioxide, may be added to reduce this.
WATER SOLUBLE AND WATER MISCIBLE
BASES
Glycero-Gelatin base
·
This is a mixture of glycerol and water made
into a stiff jelly by adding gelatin.
·
It is used for the preparation of jellies,
suppositories and pessaries. The stiffness of the mass depends upon the
proportion of gelatin used which is adjusted according to its use.
·
The base being hydrophilic in nature, slowly
dissolves in the aqueous secretions and provide a slow continuous release of
medicament. Glycerogelatin base is well suited for suppositories containing
belladonna extract, boric acid, chloral hydrate, bromides, iodides, iodoform,
opium, etc.
·
Depending upon the compatibility of the drugs
used a suitable type of gelatin is selected for the purpose. Two types of
gelatins are used as suppository base
(i) Type-A or
Pharmagel-A which is made by acid hydrolysis (has isoelectric point between 7 to 9 and on the acid
side of the range behaves as a cationic agent, being most effective at pH 7 to
8. ) is used for acidic
drugs.
(ii) Type-B or
Pharmagel-B which is prepared by alkaline hydrolysis (having an isoelectric point
between 4.7 to 5 and on the alkaline side of the range behaves as an anionic
agent, being most effective at pH 7 to 8 ) is used for alkaline drugs
Disadvantages:
Glycerogelain base suppositories
are less commonly used than the fatty base suppositories because:
(i) Glycerol
has laxative action.
(ii) They
are more difficult to prepare and handle.
(iii) Their
solution time depends on the content and quality of the gelatin and the age of
the base.
(iv) They
are hygroscope, hence must be carefully stored.
(v) Gelatin
is incompatible with drugs those precipitate with the protein e.g. tannic acid,
ferric chloride, gallic acid, etc.
Soap-Glycerin Suppositories
·
In this case gelatin and curd soap or sodium
stearate which makes the glycerin sufficiently hard for suppositories and a
large quantity of glycerin up to 95% of the mass can be incorporated.
·
Further the soap helps in the evacuation of
glycerin.
·
The soap glycerin suppositories have the disadvantage
that they are very hygroscopic, therefore they must be protected from
atmosphere and wrapped in waxed paper or tin foil.
Polyethylene glycol bases / Macrogol bases (Carbowaxes)
Depending on their molecular
weight they are available in different physical forms.
Examples of Macrogol bases:
|
|
I
|
II
|
III
|
IV
|
|
|
Macrogol 400
Macrogol 1000
Macrogol 1540
Macrogol 4000
Macrogol 6000
Water
|
-
-
-
33
47
20
|
-
-
33
-
47
20
|
20
-
33
-
47
-
|
-
75
-
25
-
-
|
|
By choosing a suitable
combination a suppository base with the desired characteristics can be
prepared.
Advantages:
1. The
mixtures generally have a melting point above 420C, hence, does not
require cool storage and they are satisfactory for use in hot climate.
2. Because
of the high melting point they do not melt in the body cavity, rather they
gradually dissolve and disperse, releasing the drug slowly.
3. They
do not stick to the wall of the mould since they contract significantly on
cooling.
EMULSIFYING BASES
These are synthetic bases and a number of proprietary
bases of very good quality are available, few of which are described below:
Witepsol
They consist of triglycerides of
saturated vegetable acids (chain length C12 to C18) with varying proportions of
partial esters.
Massa Esterium
This is another range of bases,
consisting of a mixture of di-, tri- and mono- glycerides of saturated fatty
acids with chain lengths of C11 to C17.
Massuppol
It consists of glyceryl esters
mainly of lauric acid, to which a small amount of glyceryl monostearate has
been added to improve its water absorbing
capacity.
Advantages of these bases over cocoa butter:
1. Over
heating does not alter the physical characteristics.
2. They
do not stick to the mould. They do not require previous lubrication of the
mould
3. They
solidify rapidly.
4. They
are less liable to get rancid.
5. They
can absorb fairly large amount of aqueous liquids.
FACTORS AFFECTING-ABSORPTION FROM
RECTAL SUPPOSITORIES
A. Physiologic factors
The lower hemorrhoidal veins
surrounding the colon and rectum directly goes to heart and the upper
hemorrhoidal vein connects to liver via portal vein. So more than 50 to 70% of
the drug administered rectally were found to directly passing to systemic
circulation (i.e. bypassing the liver).
pH of rectal secretion
The principal method of drug
absorption from the rectum is by passive diffusion. So a drug that remains
mostly in unionized state will be absorbed more readily. Generally weakly basic
and weakly acidic drugs remains in unionized state in the pH of rectum (6.8)
and hence, absorbed readily than the stronger base or acids.
B. Physicochemical characteristics of the drug
The sequence of events that takes
place before absorption n the anorectal area is as follows:
Drug
in vehicle ®
Drug in colon fluids ®Absorption through the rectal mucosa
§ Partition coefficient: Drugs with a high
fat to water (Ko/w) partition coefficient are liberated very slowly from the
fatty bases. So water soluble salt forms of drugs are more readily absorbed
from anorectal area.
§ Rectal fluid volume: Rectal fluid
volumes also vary in different time and in different individuals. This
influences the release rate and absorption of drug from suppository bases.
§ Physical state of medicament: When a
drug remains in suspension state in a suppository the drug particles should be
very fine, so that the effective surface area is very high and thus dissolution
rate is very high.
Solution from a
suppository will be faster when it melts quickly into a fluid of low viscosity
that spreads into thin film over a large area in the rectum.
Generally, for local action fatty base is suitable and
for systemic action water-soluble
base is better for providing the quick release desirable for systemically
active drugs.
§ Presence of surfactants: Surfactants can
both increase or decrease the absorption rate of a drug from anorectal region.
Surfactants can reduce the surface tension of the colon fluid ® help
in washing the rectal mucosa, ® new pores for
absorption will be opened ® absorption is accelerated.
C.
Physicochemical characteristics of the base and adjuvants.
§ Lower
m.p. fatty base + sodium phenobarbitone ® absorption rate is faster
than higher m.p. fatty base + sod.phenobarbitone.
§ High
molecular weight PEG bases produces faster absorption than low molecular weight
PEG base.
§ Fatty
bases may be hardened several months after molding, these increase in melting
range decrease the drug release.
§ Adjuvants
in the base changes the rheologic characteristics of the base or may affect the
dissolution of the drug.
e.g.
addition of colloidal silicon oxide to fatty base dramatically changes the
rheologic characteristics of the base.
e.g.
Salicylates were found to improve the rectal absorption of water-soluble
antibiotics in lipophilic bases.
§ Emulsifying
agents such as wool fat, wool alcohols, macrogols, stearates and polysorbates,
may be included in the suppository bases to facilitate the incorporation of
aqueous solutions. They may cause unpredictable release and absorption of a
medicament.
§ Large
amount of emulsifying agents may cause excessive foaming.
§ Strong
surface active agent may produce increased absorption of drug and may produce
toxic effects.
MANUFACTURING OF SUPPOSITORIES
Moulds
The
suppository and pessary moulds are made of metals and have four, six or twelve
cavities. By removing a screw, they can be opened longitudinally for
lubrication, extraction of the suppositories and cleaning.
[N.B. The interior of the mould should never be scrapped or
rubbed with abrasive. For cleaning they are immersed in hot water containing
detergent, wiped gently with soft cloth and rinsed thoroughly.]
Capacity of moulds: The nominal capacities of the common
moulds are 1g, 2g, 4g and 8g.
Calibration
The nominal capacity of a mould varies with the base
selected. Each mould should be calibrated before use by preparing a set of suppositories
or pessaries using the base alone, weighing the products and taking the mean
weight as the true capacity. This procedure is repeated for each base.
Displacement value
The volume of a suppository from a particular mould is
uniform but its weight will differ with the density of the base.
Definition
It is the quantity of the drug that displaces one part of
the base. e.g. Zinc oxide, D = 5.
Calculation of displacement value
Formula for calculation of the amount of base required in each mould
Lubrication of mould
If the
cavities are imperfect, i.e. poorly polished or scratched, it may be difficult
to remove the suppositories without damaging their surfaces. So lubrication of
the moulds is necessary.
In case of greasy or oily base water soluble lubricants are
required.
e.g. For cocoa butter the following lubricant solution
formula may be used:
Soft
soap 10g
Glycerol 10ml
Alcohol(90%) 50ml
For water soluble /miscible bases oily lubricant may be
used. e.g. For glycero-gelatin base liquid paraffin or arachis oil may be used
as lubricant.
Four methods are used in preparing
suppositories:
1.
Hand molding [Cold Hand Shaping]
1. Drug
is triturated in a mortar into fine powder.
2. Cocoa
butter is grated into small particles.
3. Drug
is mixed with small portion of cocoa butter in a mortar.
4. One
drop fixed vegetable oil is added to give plasticity to the mass.
5. Remainder
of the cocoa butter is added by geometric dilution (i.e. by adding the same
amount of base as is already in the mortar), triturated wit pressure. Heat
generated by trituration results in a plastic mass, which is cohesive and ready
to roll.
6. The
mass is scrapped from the mortar with a spatula and rolled into a ball.
7. An
ointment tile is taken, dusted lightly with starch powder, ball is placed on
it, rolled with a flat faced spatula to form a cylinder. The cylinder is cut
into desired number of pieces with a sharp blade.
8. One
end of a suppository is held firmly with a finger and the other end is tapered
with the spatula to give the shape of suppository.
2. Compression
molding
In this
case an instrument known as compression
mould is used.
1. Drug
is powdered and mixed with grated cocoa butter.
2. The
mixture is filled into a chilled cylinder. The mixture is pressed within the
cylinder by a piston until a pressure is felt.
3. Then
the suppositories are expelled from the cylinder.
3. Pour molding
(Fusion method)
This is
the main method of preparing suppositories.
1. Drug
is powdered in a mortar.
2. Carefully
grated cocoa butter is taken into a beaker and heated in a water bath. When 2/3rd
portion is melted the beaker is taken out of the heat source. The rest of the
mass is melted by stirring with a glass rod. [If cocoa butter is heated to
clear liquid then unstable a, and g - crystals will form and the suppositories will remain
in melted state at room temperature.]
3. Drug
is added into the beaker and stirred thoroughly to mix with the “creamy” base.
4. The
“creamy” melted base is then poured into previously lubricated mould.
5. The
mould is allowed to congeal, then placed in the refrigerator for 30 minutes to
harden (forms stable b-crystal after 24 hours of refrigeration).
6. Mould
is taken out from the refrigerator and surface is trimmed off. The mould is
opened and the suppositories are expelled out of the mould by gentle pressure
with the finger.
4. Automatic molding machine
Two types of molding machines are
available: (a) rotary molding machine and (b) straight-line molding machine
Manufacturing
cycles in rotary molding machine:
1.
Prepared mass is filled in a into a filling hopper
where it is continuously mixed and maintained at constant temperature.
2.
The suppository molds are lubricated by brushing
or spraying lubricant solution.
3.
The molten mass is filled in the molds to a slight
excess.
4.
The mass is cooled
to solidify and the excess material is scrapped
off and collected for re-use.
5.
In the ejecting section the mold is opened and the
suppositories are pushed out by steel rods.
6.
The mold is closed, and then moved to the first step of
the cycle.
The output of a typical rotary
machine ranges from 3500 to 6000 suppositories an hour.
Manufacturing
cycles in straight-line molding machine:
Here the cycle is similar to rotary
molding machine but the individual molds are carried on a track through a
cooling tunnel, where scrape-off and ejection occur.
PACKAGING OF MOLDED SUPPOSITORIES
Objective:
The suppositories should be over-wrapped, or they must be placed in a container
in such a way that they do not touch each other.
Why
packing is required?
Suppositories in contact with one
another may fuse with one another or with the container at room temperature.
Packing
materials: Suppositories are usually over-wrapped in aluminium foils, paper
strip or plastic strips.
Packaging machines
1.
Machine-I:
The chilled-hardened suppositories are placed in a notched turntable and then
fed to the packing station, where the foil is unwounded from a roll, cut to
size, and finally rolled around each suppository.
2.
Machine-II: The suppositories are enclosed in
cellophane or heal-sealed aluminium foils. Plastic may be thermoformed into two
packaging halves. Suppository is mechanically placed in one half and the second
half of plastic is sealed by heat.
Bulk storage
The individually wrapped
suppositories are packaged in slide, folding, or set-up boxes.
Suppositories containing hygroscopic
or volatile material are packed in glass or plastic containers.
Many suppositories are not
individually over-wrapped. They are placed in sectioned card-board boxes or
plastic containers to hold 6 or 12 suppositories.
In-package molding
In this automatic method individual
suppository is molded in their wrapping material. Either plastic or aluminium
foil/propylene/lacquer laminate are used.
Advantage:
If the suppository melts at higher storage temperature their shapes are
retained which can be used just by chilling again.
In plastic wrapping the plastic is thermoformed into the shape of
mould. The molten mass is injected through the top end and tops is cooled and
sealed.
In aluminium foil method two aluminium foils are embossed and sealed
to give the shape of a mold and then the mass is injected at the top and then
the top is cooled and sealed.
SPECIFIC PROBLESM IN FORMULATING
SUPPOSITORIES
1. Water in suppositories
Water is used as a solvent to incorporate a
water-soluble substance in the suppository base. Incorporating water should be avoided for the following
reasons.
(a) Water accelerates the
oxidation of fats.
(b) If the water evaporates the
dissolved substances crystallize out.
(c) In presence of water
reactions between various ingredients of suppositories may occur.
(d) The water may be contaminated
with bacteria or fungus.
3.
Hygroscopicity
Glycerinated gelatin suppositories lose moisture in
dry climates and absorbs moisture in high humidity.
Polyethylene glycol bases are also hygroscopic.
4.
Incompatibilities
Poyethylene glycol bases are incompatible with
silver salts, tannic acid, aminopyrine, quinine, ichthammol, aspirin,
benzocaine, iodochlorohydroxyquin, and sulfonamides.
Many chemicals have a tendency to crystallize out of
PEG e.g. sodium barbital, salicylic acid and camphor.
5.
Viscosity
Viscosity of melted base is low in cocoa butter and
high in PEG and glycerinated gelatin. Low viscosity base when melted the
suspended particles may sediment very quickly producing nonuniform distribution
of drugs.
Remedies:
(a) The base should be melted at
the minimum temperature required to maintain the fluidity of the base.
(b) The base is constantly
stirred in such a way that the particles cannot settle and no air is entrapped
in the suppository..
(c) A base with a narrow melting
range closer to rectal temperature is used.
(d) Inclusion of approximately 2%
aluminium monostearate increase the viscosity of the fatty base and also helps
in homogeneous suspension of particles.
(e) Cetyl, stearyl, myristyl
alcohol or stearic acid are added to improve the consistency of suppositories.
6. Brittleness
Cocoa butter base is not brittle but synthetic fat
bases with high degree of hydrogenetation and high stearate containing bases
are brittle.
Brittle suppositories produce trouble during
manufacture, handling, packaging and during use.
Causes: Rapid chilling (shock
cooling) of the melted bases in an extremely cold mold.
Remedies:
(a) The temperature difference
between the melted base and mold should be as small as possible.
(b) Addition of small amount of
Tween80, castor oil, glycerin or propylene glycol imparts plasticity to a fat
and make it less brittle.
7. Volume contraction
When the bases are cooled in the mould volume of
some bases may contract. Volume contraction produces
(a) good mold release
facilitating the ejecting from mold.
(b) contraction hole formation at
the top: This imperfection can be solved by adding slight excess base over the
suppositories and after cooled the excess is scrapped off.
8. Lubricants
Cocoa butter adheres to suppository molds because of
very low volume of contraction. Aqueous lubricant may be used to remove the
suppositories easily from the molds. They are applied by wiping, brushing or
spraying. The mold surfaces may be coated with teflon to reduce the adhesion of
base to mold wall.
9. Rancidity & oxidation
Due to auto oxidation of unsaturated fatty acids
present in the base, saturated and unsaturated aldehydes, ketones and acids may
formed, which have very strong unpleasant odor – this phenomenon is called
rancidification. To prevent this suitable antioxidants like hydroquinione, b-naphthoquinone,
a- and b-tocopherols, gossypol (present in cotton seed oil), sesamol (present in sesame oil) propyl
gallate, gallic acid, tannins and tannic acids, ascorbic acid (Vit C.),
butylated hydroxyanisole (BHA) and butylated hydroxyanisole (BHA).