Suppositories sb
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101 slides
Sep 20, 2016
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About This Presentation
Suppositories for Rectal Administration
Slide Content
Suppository
(Dr.) Mirza Salman Baig
Assistant Professor (Pharmaceutics)
AIKTC, School of Pharmacy,New Panvel
Affiliated to University of Mumbai, INDIA
(Dr.) Mirza Salman Baig
Assistant Professor (Pharmaceutics)
AIKTC, School of Pharmacy,New Panvel
Affiliated to University of Mumbai, INDIA
•
The patient is unable to use the oral
route (inflection of GIT, nausea,
unconsciousness, post-operation,
young, old and mentally disturbed
patients).
•
The drug is less suited for oral route
(causes GI side effects, insufficiently
stable at pH of GIT, susceptible to
enzymatic degradation, has first-
pass effect, with unacceptable taste)
2
The patient is unable to use the oral
route (inflection of GIT, nausea,
unconsciousness, post-operation,
young, old and mentally disturbed
patients).
•
The drug is less suited for oral route
(causes GI side effects, insufficiently
stable at pH of GIT, susceptible to
enzymatic degradation, has first-
pass effect, with unacceptable taste)
2
•
Slow and incomplete absorption.
•
Inter and intra-subject variation.
•
Problems with large scale production
of suppositories
•
Short shelf life.
•
Demanding stringent storage
conditions.
3
Slow and incomplete absorption.
•
Inter and intra-subject variation.
•
Problems with large scale production
of suppositories
•
Short shelf life.
•
Demanding stringent storage
conditions.
3
•
Local effect:
- In case of pain, itching and haemorroids
- locally active drugs include astringents,
antiseptics, local anaesthetics,
vasoconstrictors, anti-inflammatory
compounds, soothing and protective
agents and laxatives.
•
Systemic effect:
- Anti-asthmatics, anti-rheumatics and
analgesics.
4
Local effect:
- In case of pain, itching and haemorroids
- locally active drugs include astringents,
antiseptics, local anaesthetics,
vasoconstrictors, anti-inflammatory
compounds, soothing and protective
agents and laxatives.
•
Systemic effect:
- Anti-asthmatics, anti-rheumatics and
analgesics.
4
•
The rectum is about
15 to 20 cm long.
•
It hooks up with the
sigmoid colon and
with the anal canal.
•
It is a hollow organ
with a relatively flat
wall surface,
•
It dose
not have
villi
5
The rectum is about
15 to 20 cm long.
•
It hooks up with the
sigmoid colon and
with the anal canal.
•
It is a hollow organ
with a relatively flat
wall surface,
•
It dose
not have
villi
5
•
The terminal 2 to
3 cm of the
rectum is called
the anal canal.
•
The opening of
the anal canal to
the exterior is
called the anus.
6
The terminal 2 to
3 cm of the
rectum is called
the anal canal.
•
The opening of
the anal canal to
the exterior is
called the anus.
6
•
The anus is controlled by an internal
sphincter
of smooth muscle and an
external sphincter of skeletal muscle.
•
Under normal conditions, the rectum is
empty and filling provokes a defecation
reflex which under voluntary control.
•
Rectum contains (about 2 to 3 ml)
mucous, which has a pH of 7.4 and little
buffering capacity.
7
The anus is controlled by an internal
sphincter
of smooth muscle and an
external sphincter of skeletal muscle.
•
Under normal conditions, the rectum is
empty and filling provokes a defecation
reflex which under voluntary control.
•
Rectum contains (about 2 to 3 ml)
mucous, which has a pH of 7.4 and little
buffering capacity.
7
•
The rectal tissues
are drained by
the inferior,
middle and
superior
haemorrhoidal
veins, but
only
the superior
vein connects
with the
hepatic-portal
system.
8
The rectal tissues
are drained by
the inferior,
middle and
superior
haemorrhoidal
veins, but
only
the superior
vein connects
with the
hepatic-portal
system.
8
•
Medicaments absorbed in the lower
part of the rectum are delivered
directly into the systemic circulation,
thus avoiding any first-pass
metabolism
.
•
However, it has been found that
suppositories can settle high enough in
the rectum to allow at least some drug
absorption into the superior vein.
•
Thus keeping the drug in the lower part of
the rectum would be advisable.
9
Medicaments absorbed in the lower
part of the rectum are delivered
directly into the systemic circulation,
thus avoiding any first-pass
metabolism
.
•
However, it has been found that
suppositories can settle high enough in
the rectum to allow at least some drug
absorption into the superior vein.
•
Thus keeping the drug in the lower part of
the rectum would be advisable.
9
•
Insertion of a suppository into the rectum
results leads to the bioavailability of the
drug.
•
Suppository will
either dissolve in the
rectal fluid or melt
on the mucous layer.
•
Since the volume of rectal fluid is so small,
complete dissolution of the base
require
extra water
.
•
Drugs in the suppository diffuse out &
absorption will be passive diffusion
10
Insertion of a suppository into the rectum
results leads to the bioavailability of the
drug.
•
Suppository will
either dissolve in the
rectal fluid or melt
on the mucous layer.
•
Since the volume of rectal fluid is so small,
complete dissolution of the base
require
extra water
.
•
Drugs in the suppository diffuse out &
absorption will be passive diffusion
10
1- Quantity of fluids available
•
Very small volume under normal conditions
(3ml spread in a layer of approximately
100
µ
m thick over the organ).
•
Under non-physiological conditions the
volume is enlarged.
•
Thus, absorption of slightly soluble drugs (i.e.
phenytoin) will be dissolution rate limited.
11
•
Very small volume under normal conditions
(3ml spread in a layer of approximately
100
µ
m thick over the organ).
•
Under non-physiological conditions the
volume is enlarged.
•
Thus, absorption of slightly soluble drugs (i.e.
phenytoin) will be dissolution rate limited.
11
2- Properties of rectal fluids
–
Composition, viscosity, pH and surface
tension of rectal fluids have great
effects on drug bioavailability.
3- Contents of the rectum
–
Faecal content
12
–
Composition, viscosity, pH and surface
tension of rectal fluids have great
effects on drug bioavailability.
3- Contents of the rectum
–
Faecal content
12
4- Motility of the rectum
•
The rectal wall may exert a pressure on a
suppository present in the lumen by two distinct
mechanisms.
•
First, the
abdominal organs may simply press
on to the rectum
when the body in upright
position. This may stimulate spreading and promote
absorption.
•
Second, the
motility of the rectal muscle
associated with the presence of food in the colon
(waves of contractions running over the wall of the
colon)
13
•
The rectal wall may exert a pressure on a
suppository present in the lumen by two distinct
mechanisms.
•
First, the
abdominal organs may simply press
on to the rectum
when the body in upright
position. This may stimulate spreading and promote
absorption.
•
Second, the
motility of the rectal muscle
associated with the presence of food in the colon
(waves of contractions running over the wall of the
colon)
13
1- Lipid-water solubility of the drug
2- Particle size of the drug
3- degree of drug ionization
4- Nature of the base
Physicochemical factors of
the drug and the base:
14
2- Particle size of the drug
3- degree of drug ionization
4- Nature of the base
Physicochemical factors of
the drug and the base:
14
Physicochemical properties of
Suppositories Base
&
Formulation concideration
for
rectal absorption of
medicament from
suppositories
Suppositories Base
&
Formulation concideration
for
rectal absorption of
medicament from
suppositories
•
The lipid water partition coefficient of the
drug is an important consideration in the
selection of the suppository base and in
anticipating drug release from that base.
•
A
lipophilic drug
that is distributed in a
fatty suppository base in low
concentration has
less of a tendency to
escape
to the surrounding aqueous fluids
than a hydrophilic drug in its saturation
concentrations.
16
The lipid water partition coefficient of the
drug is an important consideration in the
selection of the suppository base and in
anticipating drug release from that base.
•
A
lipophilic drug
that is distributed in a
fatty suppository base in low
concentration has
less of a tendency to
escape
to the surrounding aqueous fluids
than a hydrophilic drug in its saturation
concentrations.
16
•
Water-soluble bases
dissolve in
rectal fluids and release both water-
soluble and oil-soluble drugs.
•
The more drug in the base, the more
dug will be available for potential
absorption
•
A drug with a high partition
coefficient is likely to be absorbed
more readily from a water soluble
bases.
17
Contd...
Contd...
Water-soluble bases
dissolve in
rectal fluids and release both water-
soluble and oil-soluble drugs.
•
The more drug in the base, the more
dug will be available for potential
absorption
•
A drug with a high partition
coefficient is likely to be absorbed
more readily from a water soluble
bases.
17
Contd...
Contd...
•
Absorption through rectal mucosa
proceeds in accordance with pH-
partition theory.
•
At the slightly alkaline pH of rectal
mucosa, weakly basic drugs will exist
in their lipid
–
soluble unionized form
and readily absorbed.
18
Absorption through rectal mucosa
proceeds in accordance with pH-
partition theory.
•
At the slightly alkaline pH of rectal
mucosa, weakly basic drugs will exist
in their lipid
–
soluble unionized form
and readily absorbed.
18
•
For drugs present in the suppository
in the un-dissolved form, the size will
influence the amount released and
dissolved for absorption.
•
The smaller the size, the more
readily the dissolution of the particle
and the greater the chance for rapid
absorption.
19
For drugs present in the suppository
in the un-dissolved form, the size will
influence the amount released and
dissolved for absorption.
•
The smaller the size, the more
readily the dissolution of the particle
and the greater the chance for rapid
absorption.
19
•
If the
base interacts
with the drug
inhibiting its release, drug absorption
will be impaired or even prevented.
•
If the
base is irritating
to the
mucous membranes of the rectum, it
may initiate a colonic response and
prompt a bowel movement, negating
the prospect of thorough drug
release and absorption.
20
If the
base interacts
with the drug
inhibiting its release, drug absorption
will be impaired or even prevented.
•
If the
base is irritating
to the
mucous membranes of the rectum, it
may initiate a colonic response and
prompt a bowel movement, negating
the prospect of thorough drug
release and absorption.
20
Suppositories
A suppository is a medicated solid dosage
form generally intended for use in
body
cavaties like
rectum, vagina and to a
lesser extent, the urethra.
After insertion they
melt
or soften at
body temperature, whereas vaginal
suppositories sometimes called as
pessaries
, are made t
o
disintegrate
in
body fluids.
A suppository is a medicated solid dosage
form generally intended for use in
body
cavaties like
rectum, vagina and to a
lesser extent, the urethra.
After insertion they
melt
or soften at
body temperature, whereas vaginal
suppositories sometimes called as
pessaries
, are made t
o
disintegrate
in
body fluids.
•
The medicament is incorporated into a base
such as
cocoa butter
which melts at body
temperature, or into
glycerinated gelatin
or PEG which slowly dissolves in the mucous
secretions.
•
Suppositories are suited particularly for
producing
local action
, or systemic effect
or to exert a mechanical effect to facilitate
emptying the lower bowel.
22
The medicament is incorporated into a base
such as
cocoa butter
which melts at body
temperature, or into
glycerinated gelatin
or PEG which slowly dissolves in the mucous
secretions.
•
Suppositories are suited particularly for
producing
local action
, or systemic effect
or to exert a mechanical effect to facilitate
emptying the lower bowel.
22
Sizes of suppositories
0
For Children
1,2 & 3
For rectal use
4
Pessaries
A
& B
Nasal &
urethral
bougies
0
For Children
1,2 & 3
For rectal use
4
Pessaries
A
& B
Nasal &
urethral
bougies
•
As with the ointment bases, suppository base
composition plays an important role in both the
rate and extent of release of medications.
•
Suppository bases may be classified according to
their composition and physical properties:
1- Oleaginous (fatty) bases
Ex. Cocabutter (Theobroma)
2- Water soluble or miscible
bases
Ex. Glycero-Gelatin base
/PEG
24
As with the ointment bases, suppository base
composition plays an important role in both the
rate and extent of release of medications.
•
Suppository bases may be classified according to
their composition and physical properties:
1- Oleaginous (fatty) bases
Ex. Cocabutter (Theobroma)
2- Water soluble or miscible
bases
Ex. Glycero-Gelatin base
/PEG
24
1- Origin and chemical
composition
v
The source of origin (i.e. entirely
natural or synthetic or modified
natural).
v
Physical and chemical
incompatibilities with additives
(i.e. preservatives, antioxidants
and emulsifiers)
25
composition
v
The source of origin (i.e. entirely
natural or synthetic or modified
natural).
v
Physical and chemical
incompatibilities with additives
(i.e. preservatives, antioxidants
and emulsifiers)
25
2- Melting range
v
Since fats do not have sharp
melting point, their melting
characteristics are expressed as a
range indicating the temperature
at which the fat start to melt and
the temperature at which it is
completely melted.
v
Softening point.
26
v
Since fats do not have sharp
melting point, their melting
characteristics are expressed as a
range indicating the temperature
at which the fat start to melt and
the temperature at which it is
completely melted.
v
Softening point.
26
3- Solidi Fat Index (SFI)
v
Graph isplotted between
%solid vs temperature
v
Base with sharp drop of
curve is brittle.
v
This require reduced
temperature differential
between mould and base.
v
SFI is determined by
dilatometry.
27
v
Graph isplotted between
%solid vs temperature
v
Base with sharp drop of
curve is brittle.
v
This require reduced
temperature differential
between mould and base.
v
SFI is determined by
dilatometry.
27
4- Hydroxyl value
v
This value give quantity of momo and
diglycerides present in oleogeneous base.
v
Miligram of KOH required to nutralize
unreacted acetic acid.
28
v
This value give quantity of momo and
diglycerides present in oleogeneous base.
v
Miligram of KOH required to nutralize
unreacted acetic acid.
28
5- Solidification point
v
This value indicates the time required for
base solidification when it is chilled in the
mold.
v
If the interval between the melting range
and solidification point is 10
º
C or more,
the
time required for solidification
may have to be shortened for a more
efficient manufacturing
procedure by
augmenting (
increasing
) refrigeration.
29
v
This value indicates the time required for
base solidification when it is chilled in the
mold.
v
If the interval between the melting range
and solidification point is 10
º
C or more,
the
time required for solidification
may have to be shortened for a more
efficient manufacturing
procedure by
augmenting (
increasing
) refrigeration.
29
6- Saponification value
v
The number of milligrams of
potassium hydroxide required to
neutralize the free fatty acids
and to saponify the esters contained
in 1 gm of fat
v
It is an indication of the type of
glyceride (mono- or tri-) as well as
the amount of glyceride present.
30
v
The number of milligrams of
potassium hydroxide required to
neutralize the free fatty acids
and to saponify the esters contained
in 1 gm of fat
v
It is an indication of the type of
glyceride (mono- or tri-) as well as
the amount of glyceride present.
30
7- Iodine value
v
This value express the number
of grams of iodine that react with
100 gm of fat or other
unsaturated material.
v
The possibility of decomposition
by moisture, acids, and oxygen
(leads to rancidity in fats)
increases with high iodine values.
31
v
This value express the number
of grams of iodine that react with
100 gm of fat or other
unsaturated material.
v
The possibility of decomposition
by moisture, acids, and oxygen
(leads to rancidity in fats)
increases with high iodine values.
31
8- Water number
v
The amount of water in grams,
which can be incorporated in 100
gm of fat is expressed by this
value.
v
The water number can be
increased by addition of surface
active agents.
32
v
The amount of water in grams,
which can be incorporated in 100
gm of fat is expressed by this
value.
v
The water number can be
increased by addition of surface
active agents.
32
9- Acid value
v
The number of milligrams of KOH required
to neutralize the free acid in 1 gm of
substance is expressed by this value.
v
Low acid values or complete absence
of acid are important for good
suppository bases.
v
Free acids complicate formulation work,
because they react with other ingredients
and can also cause irritation when in
contact with mucous membranes.
33
v
The number of milligrams of KOH required
to neutralize the free acid in 1 gm of
substance is expressed by this value.
v
Low acid values or complete absence
of acid are important for good
suppository bases.
v
Free acids complicate formulation work,
because they react with other ingredients
and can also cause irritation when in
contact with mucous membranes.
33
Ideal Suppository Base
The ideal suppository base should be
•
Nontoxic
and
nonirritating
to sensitive and
inflamed tissues.
•
Non sensitizing (allergic)
•
Inert and
compatible
with a broad variety of
medicaments.
•
Can be easily manufactured by
compression or
molding
.
•
It has
no meta-stable forms
.
•
Dissolve
or disintegrate in the presence of mucous
secretions or
melt
at body temperature ( 36
0
C) to
allow for the release of the medication.
35
Ideal Suppository Base
•
Nontoxic
and
nonirritating
to sensitive and
inflamed tissues.
•
Non sensitizing (allergic)
•
Inert and
compatible
with a broad variety of
medicaments.
•
Can be easily manufactured by
compression or
molding
.
•
It has
no meta-stable forms
.
•
Dissolve
or disintegrate in the presence of mucous
secretions or
melt
at body temperature ( 36
0
C) to
allow for the release of the medication.
35
Ideal Suppository Base
Ideal Suppository Base
•
Remain molten for a sufficient period of
time to allow pouring into moulds.
•
Solidify
sufficiently rapidly to minimize
sedimentation of dispersed solids.
•
Shrink on cooling
to allow easy
withdrawal of the suppository from the
mould.
•
Has
wetting
and emulsifying properties.
•
High water number
.
•
Stable
on storage, does not change color,
odor and drug release pattern
.
•
Remain molten for a sufficient period of
time to allow pouring into moulds.
•
Solidify
sufficiently rapidly to minimize
sedimentation of dispersed solids.
•
Shrink on cooling
to allow easy
withdrawal of the suppository from the
mould.
•
Has
wetting
and emulsifying properties.
•
High water number
.
•
Stable
on storage, does not change color,
odor and drug release pattern
.
If the base is
fatty
, it has the
following additional requirements:
•
Acid value is below 0.2.
•
Saponification value ranges from 200
to 245.
•
Iodine value is less than 7.
•
The interval between melting point
and solidification point is small.
37
fatty
, it has the
following additional requirements:
•
Acid value is below 0.2.
•
Saponification value ranges from 200
to 245.
•
Iodine value is less than 7.
•
The interval between melting point
and solidification point is small.
37
Include:
•
Theobroma Oil
•
Synthetic
triglyceride
mixtures.
38
•
Theobroma Oil
•
Synthetic
triglyceride
mixtures.
38
v
Theobroma Oil
or
cocoa butter
is used as a
suppository base because, in large measure, it
fulfills the requirements of an ideal base.
v
Cocoa butter is primarily a tri-glyceride (Oleopal
mitostearin) , it is yellowish- white, solid, brittle
fat, which smells and tastes like chocolate.
v
At ordinary room temperatures of 15
°
to 25
°
C it
is a hard, amorphous solid,
v
It melt at 30
°
to 35
°
C i.e., at body temperature,
it melts to a bland, nonirritating oil.
39
Theobroma Oil
or
cocoa butter
is used as a
suppository base because, in large measure, it
fulfills the requirements of an ideal base.
v
Cocoa butter is primarily a tri-glyceride (Oleopal
mitostearin) , it is yellowish- white, solid, brittle
fat, which smells and tastes like chocolate.
v
At ordinary room temperatures of 15
°
to 25
°
C it
is a hard, amorphous solid,
v
It melt at 30
°
to 35
°
C i.e., at body temperature,
it melts to a bland, nonirritating oil.
39
v
Thus in warm climates, theobroma
oil suppositories should be
refrigerated.
v
Cocoa butter has iodine value
between 34 and 38.
v
Its acid value not higher than 4.
40
Thus in warm climates, theobroma
oil suppositories should be
refrigerated.
v
Cocoa butter has iodine value
between 34 and 38.
v
Its acid value not higher than 4.
40
q
Shrinks only slightly on solidification; a mould
lubricant
is therefore required.
q
Exists in four polymorphic forms with different
melting points
q
Alfa 24
q
Beta' 28-31
q
Beta (stable) 34-35 (beta' sloly changes to beta
stable)
q
Gamma 18
q
Theobroma should only be heated for a short time
and at temperatures just below 36
º
C in order
to
minimize the formation of the unstable
low
melting point forms.
41
Shrinks only slightly on solidification; a mould
lubricant
is therefore required.
q
Exists in four polymorphic forms with different
melting points
q
Alfa 24
q
Beta' 28-31
q
Beta (stable) 34-35 (beta' sloly changes to beta
stable)
q
Gamma 18
q
Theobroma should only be heated for a short time
and at temperatures just below 36
º
C in order
to
minimize the formation of the unstable
low
melting point forms.
41
q
Theobroma oil is prone to
oxidation
(due to high iodine value); this can
be partly overcome by storage in a
cool, dark place.
q
Theobroma oil may vary in
consistency, odor, and color
depending on its source like other
natural products.
q
The low melting point of theobroma
oil may pose storage problems in hot
climates.
42
Theobroma oil is prone to
oxidation
(due to high iodine value); this can
be partly overcome by storage in a
cool, dark place.
q
Theobroma oil may vary in
consistency, odor, and color
depending on its source like other
natural products.
q
The low melting point of theobroma
oil may pose storage problems in hot
climates.
42
How formation of unstable
form of polymorphs can be
avoided?
•
If mass is not completly melted,
remaining crystal prevent formation
of unstable crystal.
•
Seeding
•
Solidified mass is tempered at
28
0
-32
0
C to convert Beta'--> Beta
Stable.
•
Prolonged heating and overheating
must be avoided.
form of polymorphs can be
avoided?
•
If mass is not completly melted,
remaining crystal prevent formation
of unstable crystal.
•
Seeding
•
Solidified mass is tempered at
28
0
-32
0
C to convert Beta'--> Beta
Stable.
•
Prolonged heating and overheating
must be avoided.
Additives
•
Wax/Spermaceti added to keep
melting point at 35 when drug used
is volatile which can redduce melting
point.
•
Emulsifier to increase water holding
capicity.
•
Wax/Spermaceti added to keep
melting point at 35 when drug used
is volatile which can redduce melting
point.
•
Emulsifier to increase water holding
capicity.
q
The change (reduction) in melting point caused
by addition of certain drugs such as volatile oils,
phenol or chloral hydrate to cocoa butter
suppositories. The remedy is to raise the melting
point back to the desired range by addition of 3%
to 5% of beeswax or spermaceti.
q
Theobroma oil has a
low absorptive
capacity
for water, but this can be increased by adding
surfactants such as cholesterol 2%, emulsifying
wax up to 10%, polysorbates 5 to 10%, or wool
fat 5 to 10%. However, the addition of
surfactants may lead to a drug- base interaction
or affect the release of drug from suppository.
45
Additives contd...
The change (reduction) in melting point caused
by addition of certain drugs such as volatile oils,
phenol or chloral hydrate to cocoa butter
suppositories. The remedy is to raise the melting
point back to the desired range by addition of 3%
to 5% of beeswax or spermaceti.
q
Theobroma oil has a
low absorptive
capacity
for water, but this can be increased by adding
surfactants such as cholesterol 2%, emulsifying
wax up to 10%, polysorbates 5 to 10%, or wool
fat 5 to 10%. However, the addition of
surfactants may lead to a drug- base interaction
or affect the release of drug from suppository.
45
Additives contd...
Substitutes of cocabutter
•
Synthetic triglycerides
•
Palm kernel oil
•
Hydrogenated corn oil
•
Synthetic triglycerides
•
Palm kernel oil
•
Hydrogenated corn oil
q
The newer
synthetic tri-glycerides
consist of
esterified, hydrogenated or fractionated
vegetable oils.
q
Their advantages over cocoa butter are:
1- Do not exhibit polymorphism.
2- Contain mainly saturated acids (Iodine number
<3), while cocoa butter contains considerable
amount of the unsaturated fatty acids (Iodine
number 34-38).
47
The newer
synthetic tri-glycerides
consist of
esterified, hydrogenated or fractionated
vegetable oils.
q
Their advantages over cocoa butter are:
1- Do not exhibit polymorphism.
2- Contain mainly saturated acids (Iodine number
<3), while cocoa butter contains considerable
amount of the unsaturated fatty acids (Iodine
number 34-38).
47
3-
The melting range of the synthetic bases is
usually about 3
º
C higher than that of cocoa
butter
4-
The acid content is lower (mostly <0.5)
5-
hard fat is a mixture of mono, di and tri-
glycerides of saturated fatty acids (C
10
to
C
18
).
The hydroxyl value
of a base is
determined by the proportions of mono and
di-glycerides contained in it. A higher
hydroxyl value indicates that the base can
absorb water more readily and less suitable
to easily hydrolyzed drugs.
48
The melting range of the synthetic bases is
usually about 3
º
C higher than that of cocoa
butter
4-
The acid content is lower (mostly <0.5)
5-
hard fat is a mixture of mono, di and tri-
glycerides of saturated fatty acids (C
10
to
C
18
).
The hydroxyl value
of a base is
determined by the proportions of mono and
di-glycerides contained in it. A higher
hydroxyl value indicates that the base can
absorb water more readily and less suitable
to easily hydrolyzed drugs.
48
6-
The solidification temperatures of hard fats are
unaffected by over heating.
7-
There is only a small temperature difference
between melting and solidification, thus the
sedimentation of suspended drugs is minimized.
8-
The water absorbing capacity of hard fats can
be improved (to about 25% or 30% w/w) by
inclusion of glyceryl monostearate.
49
The solidification temperatures of hard fats are
unaffected by over heating.
7-
There is only a small temperature difference
between melting and solidification, thus the
sedimentation of suspended drugs is minimized.
8-
The water absorbing capacity of hard fats can
be improved (to about 25% or 30% w/w) by
inclusion of glyceryl monostearate.
49
q
A tendency to fracture upon pouring into
chilled moulds can be overcome by
including very small quantities of
polysorbate 80.
q
On prolonged storage, synthetic
suppository bases have been shown to
be subjected to crystallization, which
causes hardening and increases the
melting time. This can be reduced by
storage in a cold place.
50
A tendency to fracture upon pouring into
chilled moulds can be overcome by
including very small quantities of
polysorbate 80.
q
On prolonged storage, synthetic
suppository bases have been shown to
be subjected to crystallization, which
causes hardening and increases the
melting time. This can be reduced by
storage in a cold place.
50
A.
Glycerinated
gelatin
B.
Polyethylene
glycol (PEG)
polymers.
51
Hydrophilic suppositories base
Glycerinated
gelatin
B.
Polyethylene
glycol (PEG)
polymers.
51
Hydrophilic suppositories base
v
Glycerinated Gelatin
is a useful
suppository base, particularly for vaginal
suppositories, where the
prolonged
localized action
is usually desired.
v
Glycerinated gelatin suppositories are
translucent, resilient, gelatinous solids
that tend to dissolve in mucous
secretions to provide prolonged release
of active ingredients.
v
It is suitable for use with a
wide range
of medicaments
including alkaloids,
boric acid, and zinc oxide.
52
Glycerinated Gelatin
is a useful
suppository base, particularly for vaginal
suppositories, where the
prolonged
localized action
is usually desired.
v
Glycerinated gelatin suppositories are
translucent, resilient, gelatinous solids
that tend to dissolve in mucous
secretions to provide prolonged release
of active ingredients.
v
It is suitable for use with a
wide range
of medicaments
including alkaloids,
boric acid, and zinc oxide.
52
v
Suppositories made with glycerinated
gelatin must be kept in
well-closed
containers
in a cool place since they will
absorb and dissolve in
atmospheric
moisture
.
v
Suppositories may have a
dehydrating
effect
and be irritating to the tissues upon
insertion.
v
The water present in the formula of
suppositories minimizes this action and the
suppositories may be moistened with water
prior to insertion to reduce the tendency of
the base to draw water from mucous.
53
Contd...
Contd...
Suppositories made with glycerinated
gelatin must be kept in
well-closed
containers
in a cool place since they will
absorb and dissolve in
atmospheric
moisture
.
v
Suppositories may have a
dehydrating
effect
and be irritating to the tissues upon
insertion.
v
The water present in the formula of
suppositories minimizes this action and the
suppositories may be moistened with water
prior to insertion to reduce the tendency of
the base to draw water from mucous.
53
Contd...
Contd...
•
Mix or dissolve the medicaments in water
to make a total of 10 g.
•
Add 70 g of glycerin and mix.
•
Add 20 g of granular gelatin, mix carefully
to avoid incorporation of air.
•
Heat on a steam bath until the gelatin is
dissolved.
•
Pour the melted mixture into molds and
allow to congeal.
54
Mix or dissolve the medicaments in water
to make a total of 10 g.
•
Add 70 g of glycerin and mix.
•
Add 20 g of granular gelatin, mix carefully
to avoid incorporation of air.
•
Heat on a steam bath until the gelatin is
dissolved.
•
Pour the melted mixture into molds and
allow to congeal.
54
•
The gelatin constitutes about 60% of
the weight of the formula, the
glycerin about 20%, and the
medicated aqueous portion about
20%.
55
The gelatin constitutes about 60% of
the weight of the formula, the
glycerin about 20%, and the
medicated aqueous portion about
20%.
55
q
Polyethylene Glycol Polymers
are
chemically stable, nonirritating, miscible
with water and mucous secretions, and
can be formulated, either by molding or
compression, in a wide range of hardness
and melting point.
56
Polyethylene Glycol Polymers
are
chemically stable, nonirritating, miscible
with water and mucous secretions, and
can be formulated, either by molding or
compression, in a wide range of hardness
and melting point.
56
q
Like glycerinated gelatin, they do not melt
at body temperature, but
dissolve
to
provide a more prolonged release than
theobroma oil.
q
Certain polyethylene glycol polymers may
be used singly as suppository bases
q
Some times
more molecular weights
PEG mixed
in various proportions as
needed to yield a finished product of
satisfactory hardness and dissolution
time
.
57
PEG Contd...
PEG Contd...
Like glycerinated gelatin, they do not melt
at body temperature, but
dissolve
to
provide a more prolonged release than
theobroma oil.
q
Certain polyethylene glycol polymers may
be used singly as suppository bases
q
Some times
more molecular weights
PEG mixed
in various proportions as
needed to yield a finished product of
satisfactory hardness and dissolution
time
.
57
PEG Contd...
PEG Contd...
q
PEGs having average molecular weights of
200, 400 and 600 are clear, colorless
liquids.
q
Those having molecular weights of
greater than 1000 are wax-like, white
solids with hardness increasing with an
increase in the molecular weight.
q
Since the water miscible suppositories
dissolve in body fluids and
need not be
formulated to melt at body
temperature
, they can be formulated
with much
higher melting points
.
58
PEG Contd...
PEG Contd...
PEGs having average molecular weights of
200, 400 and 600 are clear, colorless
liquids.
q
Those having molecular weights of
greater than 1000 are wax-like, white
solids with hardness increasing with an
increase in the molecular weight.
q
Since the water miscible suppositories
dissolve in body fluids and
need not be
formulated to melt at body
temperature
, they can be formulated
with much
higher melting points
.
58
PEG Contd...
PEG Contd...
q
This property permits a
slower release
of medicaments
from the base, safe
storage at room temperature without need
for refrigeration, and ease and slow
insertion.
q
To prevent irritation of the mucous
membranes after insertion of PEGs
suppositories, they
should contain at
least 20% of wate
r or dipped in water
just prior to use.
59
PEG Contd...
PEG Contd...
This property permits a
slower release
of medicaments
from the base, safe
storage at room temperature without need
for refrigeration, and ease and slow
insertion.
q
To prevent irritation of the mucous
membranes after insertion of PEGs
suppositories, they
should contain at
least 20% of wate
r or dipped in water
just prior to use.
59
PEG Contd...
PEG Contd...
1450
1450
8000
8000
300
300
8000
8000
30%
30%
70%
70%
60%
60%
40%
40%
300
300
6000
6000
1000
1000
3350
3350
1000
1000
3350
3350
48%
48%
52%
52%
95%
95%
5%
5%
75%
75%
25%
25%
60
1450
8000
8000
300
300
8000
8000
30%
30%
70%
70%
60%
60%
40%
40%
300
300
6000
6000
1000
1000
3350
3350
1000
1000
3350
3350
48%
48%
52%
52%
95%
95%
5%
5%
75%
75%
25%
25%
60
•
Chemical or physical Mixtures of oleaginous and
water soluble or water miscible materials.
•
Emulsions, generally of w/o type
(i.e. mixing
of cocoa butter with emulsifying agents).
•
Polyoxyl 40 stearate
is a mixture of the mono-
stearate and di-stearate esters of mixed poly-
oxyethylene diols and the free glycols.
•
Soap may be used as a base
(i.e. Glycerin
suppositories, USP, with soap as the base).
61
Chemical or physical Mixtures of oleaginous and
water soluble or water miscible materials.
•
Emulsions, generally of w/o type
(i.e. mixing
of cocoa butter with emulsifying agents).
•
Polyoxyl 40 stearate
is a mixture of the mono-
stearate and di-stearate esters of mixed poly-
oxyethylene diols and the free glycols.
•
Soap may be used as a base
(i.e. Glycerin
suppositories, USP, with soap as the base).
61
Suppositories can be extemporaneously
prepared by one of three methods.
1. Hand Rolling
•
It is the oldest and simplest method of
suppository preparation and may be
used when only a few suppositories are
to be prepared in a cocoa butter base.
•
It has the advantage of avoiding the
necessity of heating the cocoa butter.
•
A plastic-like mass is prepared by
triturating grated (pulverized) cocoa
butter and active ingredients in a
mortar.
62
prepared by one of three methods.
1. Hand Rolling
•
It is the oldest and simplest method of
suppository preparation and may be
used when only a few suppositories are
to be prepared in a cocoa butter base.
•
It has the advantage of avoiding the
necessity of heating the cocoa butter.
•
A plastic-like mass is prepared by
triturating grated (pulverized) cocoa
butter and active ingredients in a
mortar.
62
•
The mass is formed into a ball in the palm of
the hands, then rolled into a uniform cylinder
with a large spatula or small flat board on a pill
tile.
•
The
cylinder is then cut into the
appropriate number of pieces
which are
rolled on one end to produce a conical shape.
•
Effective hand rolling requires considerable
practice and skill.
63
The mass is formed into a ball in the palm of
the hands, then rolled into a uniform cylinder
with a large spatula or small flat board on a pill
tile.
•
The
cylinder is then cut into the
appropriate number of pieces
which are
rolled on one end to produce a conical shape.
•
Effective hand rolling requires considerable
practice and skill.
63
•
Compression molding is a method of
preparing suppositories from a mixed mass
of grated suppository base and
medicaments which is
forced into a
special compression mold
using
suppository making machines.
•
The suppository base and the other
ingredients are combined by thorough
mixing.
•
The friction of the process causing the base
to soften into a past-like consistency.
64
Compression molding is a method of
preparing suppositories from a mixed mass
of grated suppository base and
medicaments which is
forced into a
special compression mold
using
suppository making machines.
•
The suppository base and the other
ingredients are combined by thorough
mixing.
•
The friction of the process causing the base
to soften into a past-like consistency.
64
•
On large scale, mechanically operated mixers
and a warmed mixing vessels are used.
•
In
the compression machine, the
suppository mass is placed into a
cylinder which is then closed.
•
Pressure is applied from one end
to
release the mass from the other end into the
suppository mold or die.
65
Contd...
Contd...
On large scale, mechanically operated mixers
and a warmed mixing vessels are used.
•
In
the compression machine, the
suppository mass is placed into a
cylinder which is then closed.
•
Pressure is applied from one end
to
release the mass from the other end into the
suppository mold or die.
65
Contd...
Contd...
Compression molding machine
•
Prepared mass C is placed
in a cylinder A
•
It is forced through narrow
opening D by means of piston
B into a mould.
•
Threads of mass pass in the
mould G and are compressed
until a
homogenous fused
mass is formed in E.
•
The mass and compression
cylinder of the
machine may
be chilled to prevent heat
of compression
from
making the mass too fluid.
•
Prepared mass C is placed
in a cylinder A
•
It is forced through narrow
opening D by means of piston
B into a mould.
•
Threads of mass pass in the
mould G and are compressed
until a
homogenous fused
mass is formed in E.
•
The mass and compression
cylinder of the
machine may
be chilled to prevent heat
of compression
from
making the mass too fluid.
•
When the die is filled with the mass,
a movable end
'plate-F'
at the back
of the die is removed
•
Additional pressure is applied to eject
suppository
67
Contd...
Contd...
When the die is filled with the mass,
a movable end
'plate-F'
at the back
of the die is removed
•
Additional pressure is applied to eject
suppository
67
Contd...
Contd...
•
Fusion Molding involves:
1- Melting the suppository base
2- Dispersing or dissolving the drug in the melted
base.
3- The mixture is removed from the heat and
poured into a suppository mold.
4- Allowing the melt to congeal
5- Removing the formed suppositories from the
mold.
•
The fusion method can be used with all types of
suppositories and must be used with most of them.
68
Fusion Molding involves:
1- Melting the suppository base
2- Dispersing or dissolving the drug in the melted
base.
3- The mixture is removed from the heat and
poured into a suppository mold.
4- Allowing the melt to congeal
5- Removing the formed suppositories from the
mold.
•
The fusion method can be used with all types of
suppositories and must be used with most of them.
68
Contd...
•
Small scale molds
are capable of
producing 6 or 12
suppositories in a
single operation.
•
Industrial molds
produce hundreds of
suppositories from a
single molding.
70
Small scale molds
are capable of
producing 6 or 12
suppositories in a
single operation.
•
Industrial molds
produce hundreds of
suppositories from a
single molding.
70
•
Depending on the formulation,
suppository molds may require
lubrication before the melt is poured to
facilitate the clean and easy removal of
the molded suppository.
•
Lubrication is seldom necessary when
the suppository base is contracting
sufficiently on cooling.
•
Lubrication is usually necessary when
glycerinated gelatin suppositories are
prepared.
71
Depending on the formulation,
suppository molds may require
lubrication before the melt is poured to
facilitate the clean and easy removal of
the molded suppository.
•
Lubrication is seldom necessary when
the suppository base is contracting
sufficiently on cooling.
•
Lubrication is usually necessary when
glycerinated gelatin suppositories are
prepared.
71
Automatic moulding machine
•
it can make 10000
unit/hr
•
it can make 10000
unit/hr
Formulation concideration
•
For local use / Systematic use?
•
Site of application,
rectal/vaginal/urethral?
•
Quick release/ prolonged release?
•
For local use / Systematic use?
•
Site of application,
rectal/vaginal/urethral?
•
Quick release/ prolonged release?
Suppositories for systemic effect
1.
Should have
sufficient absorption
from particular
body cavity (if for systemic use)
2.
Best suited for
drugs undergoing first pass
metabolism
, degrade in GI fluids or irritate the GI
mucosa
3.
Should be
easily dispersible or soluble
in the base
4.
Should be soluble to
achieve homogeneity
but
should not have more affinity for the base or else it
wouldn't get released
5.
Particle size should be less
to improve
bioavailability and decrease irritation
6.
Density and solubility of the drug should ensure
minimum usage of base.
7.
Drug should be compatible and stable in base and at
processing conditions
8.
Water soluble drug added in oil soluble base and vice
versa
1.
Should have
sufficient absorption
from particular
body cavity (if for systemic use)
2.
Best suited for
drugs undergoing first pass
metabolism
, degrade in GI fluids or irritate the GI
mucosa
3.
Should be
easily dispersible or soluble
in the base
4.
Should be soluble to
achieve homogeneity
but
should not have more affinity for the base or else it
wouldn't get released
5.
Particle size should be less
to improve
bioavailability and decrease irritation
6.
Density and solubility of the drug should ensure
minimum usage of base.
7.
Drug should be compatible and stable in base and at
processing conditions
8.
Water soluble drug added in oil soluble base and vice
versa
Contd...
•
Suppositories for Local effect
–
Nonabsorbable drug
–
Nonabsorbable base
–
Slow melting base
–
Should melt within 4-6 hour
•
Suppositories for Local effect
–
Nonabsorbable drug
–
Nonabsorbable base
–
Slow melting base
–
Should melt within 4-6 hour
Problems in formulation of
suppositories
•
Water in Suppositories
•
Hygroscopicity
•
Incompatibilities
•
Viscosity
•
Brittelness
•
Density
•
Volume contraction
•
Lubrication
•
Dose replacement
•
Wt. and volume control
•
Rancidity/antioxidant
suppositories
•
Water in Suppositories
•
Hygroscopicity
•
Incompatibilities
•
Viscosity
•
Brittelness
•
Density
•
Volume contraction
•
Lubrication
•
Dose replacement
•
Wt. and volume control
•
Rancidity/antioxidant
1
.
Water in suppositories
Formulators do not like to use water for dissolving
drugs in suppositories for the following reasons :
a)
Water causes hydrolysis
of fats
.
b)
If the suppositories are manufactured at a high
temperature, the water evaporates, the
drugs
crystallize
out.
c)
Absorption of water soluble drugs is enhanced only
if the base is an oil
–
in
–
water
emulsion
d)
And more than
50% of the water should be in
the external phase
.
e)
Drug excipient interactions
are more likely to
happen in the presence of water.
f)
Bacterial contamination
may be a problem, so
we may be forced to add a preservative.
.
Water in suppositories
Formulators do not like to use water for dissolving
drugs in suppositories for the following reasons :
a)
Water causes hydrolysis
of fats
.
b)
If the suppositories are manufactured at a high
temperature, the water evaporates, the
drugs
crystallize
out.
c)
Absorption of water soluble drugs is enhanced only
if the base is an oil
–
in
–
water
emulsion
d)
And more than
50% of the water should be in
the external phase
.
e)
Drug excipient interactions
are more likely to
happen in the presence of water.
f)
Bacterial contamination
may be a problem, so
we may be forced to add a preservative.
2.
Hygroscopicity
•
Glycerogelatin suppositories lose moisture
in dry climates and absorb moisture in
humid conditions
•
The hygroscopicity of polyethylene glycol
bases depends on the chain length of the
molecule
•
As the molecular weight of these ethylene
oxide polymers increases the
hygroscopicity decreases
Hygroscopicity
•
Glycerogelatin suppositories lose moisture
in dry climates and absorb moisture in
humid conditions
•
The hygroscopicity of polyethylene glycol
bases depends on the chain length of the
molecule
•
As the molecular weight of these ethylene
oxide polymers increases the
hygroscopicity decreases
3.
Drug-excipient interactions
•
Incompatibilities exist between
polyethylene
glycol base and some
drugs
eg. quinine.
•
Sodium barbital and
salicylic acid
crystallize out of polyethylene glycol
.
•
High concentrations of
salicylic acid
soften polyethylene glycol
to an
ointment like consistency.
•
Penicillin G
is stable in cocoa butter and
other fatty bases but
decomposes in
polyethylene glycol bases
.
Drug-excipient interactions
•
Incompatibilities exist between
polyethylene
glycol base and some
drugs
eg. quinine.
•
Sodium barbital and
salicylic acid
crystallize out of polyethylene glycol
.
•
High concentrations of
salicylic acid
soften polyethylene glycol
to an
ointment like consistency.
•
Penicillin G
is stable in cocoa butter and
other fatty bases but
decomposes in
polyethylene glycol bases
.
4.
Viscosity
•
When the base has low viscosity,
sedimentation of the drug before
solidification is a problem.
•
Well mixed mass should be handelled
at lowest possible temperature.
•
2%
aluminium monostearate
may
be added to increase the viscosity of
the base
•
Cetyl and
stearyl alcohols
or stearic
acid are added to improve the
consistency of suppositories
Viscosity
•
When the base has low viscosity,
sedimentation of the drug before
solidification is a problem.
•
Well mixed mass should be handelled
at lowest possible temperature.
•
2%
aluminium monostearate
may
be added to increase the viscosity of
the base
•
Cetyl and
stearyl alcohols
or stearic
acid are added to improve the
consistency of suppositories
5.
Brittleness
•
Cocoa butter suppositories are elastic,
not brittle
•
Synthetic fat bases are brittle
•
This problem can be overcome by
keeping the
temperature difference
between the melted base and the
mold as
small
as possible
•
Materials that impart plasticity
to a
fat and make them less brittle are
small amounts of Tween 80, castor oil,
glycerin or propylene glycol
Brittleness
•
Cocoa butter suppositories are elastic,
not brittle
•
Synthetic fat bases are brittle
•
This problem can be overcome by
keeping the
temperature difference
between the melted base and the
mold as
small
as possible
•
Materials that impart plasticity
to a
fat and make them less brittle are
small amounts of Tween 80, castor oil,
glycerin or propylene glycol
6.
Density
•
Density of the base, the drug, the
volume of the mould and whether the
base is having the property of volume
contraction are all important.
•
They all determine the weight of the
suppository
Density
•
Density of the base, the drug, the
volume of the mould and whether the
base is having the property of volume
contraction are all important.
•
They all determine the weight of the
suppository
7.
Volume contraction
•
Because of volume contraction suppositoray esily slip
away from the mould, preventing the need for a
lubricating agent.
•
When the suppository mass is contracting, a hole
forms at the open end, This gives an inelegant
appearance to the suppository. Weight variation
among suppositories is also likely to occur.
•
To avoid this problem of volume contraction
•
Overfill the molds, and scrape off the excess mass
which contains the contraction hole
•
Pour the suppository mass slightly above its
congealing temperature into a mould warmed to
about the same temperature.
Volume contraction
•
Because of volume contraction suppositoray esily slip
away from the mould, preventing the need for a
lubricating agent.
•
When the suppository mass is contracting, a hole
forms at the open end, This gives an inelegant
appearance to the suppository. Weight variation
among suppositories is also likely to occur.
•
To avoid this problem of volume contraction
•
Overfill the molds, and scrape off the excess mass
which contains the contraction hole
•
Pour the suppository mass slightly above its
congealing temperature into a mould warmed to
about the same temperature.
Displacement value
•
The displacement value is defined as the
number of gram of ingredients (or Drug) that
displace one gram of Suppository base
•
The volume of suppositories from a particular mould
will be constant but the weight will vary because the
densities of the medicaments usually differ from the
density of the base, and hence the density of the
medicament will affect the amount of the base
required for each suppository
•
f=[100(E-G)/GX]+1
f=replacement factor
E= wt of pure base suppository
G= wt of suppository withh X% of drug
•
The displacement value is defined as the
number of gram of ingredients (or Drug) that
displace one gram of Suppository base
•
The volume of suppositories from a particular mould
will be constant but the weight will vary because the
densities of the medicaments usually differ from the
density of the base, and hence the density of the
medicament will affect the amount of the base
required for each suppository
•
f=[100(E-G)/GX]+1
f=replacement factor
E= wt of pure base suppository
G= wt of suppository withh X% of drug
Example 1
If a prescription requires 400 mg of bismuth subgallate per suppository weighing two
grams, what would be the displacement value if it is known that six suppositories
with required bismuth subgallate weigh 13.6 g?
Theoretical weight of six cocoa butter suppositories without bismuth subgallate = 12 g
Given weight of six cocoa butter suppositories
with bismuth subgallate
=13.6 g
Wt. of bismuth subgallate in the six suppositories = 0.4
×
6 =
2.4 g
Wt. of cocoa butter in the bismuth subgallate suppositories = 13.6
−
2.4 = 11.2 g
Cocoa butter displaced by 2.4 g of bismuth subgallate
= 12
−
11.2 =
0.8
The
displacement value
of bismuth subgallate is
2.4/0.8
= 3
If a prescription requires 400 mg of bismuth subgallate per suppository weighing two
grams, what would be the displacement value if it is known that six suppositories
with required bismuth subgallate weigh 13.6 g?
Theoretical weight of six cocoa butter suppositories without bismuth subgallate = 12 g
Given weight of six cocoa butter suppositories
with bismuth subgallate
=13.6 g
Wt. of bismuth subgallate in the six suppositories = 0.4
×
6 =
2.4 g
Wt. of cocoa butter in the bismuth subgallate suppositories = 13.6
−
2.4 = 11.2 g
Cocoa butter displaced by 2.4 g of bismuth subgallate
= 12
−
11.2 =
0.8
The
displacement value
of bismuth subgallate is
2.4/0.8
= 3
Example 2
•
If 12 cocoa butter suppositories containing 40% zinc oxide weigh
17.6 grams,what is the displacement value of zinc oxide? Assume
that the suppositories are made in a 1-g mold
•
Given weight of 12 suppositories with zinc oxide = 17.6 grams
•
Weight of zinc oxide in the suppositories
=
(40/100)
×
17.6 = 7.04 g
•
Weight of cocoa butter in the suppositories
= (
60
/100)
×
17.6 = 10.56 g
•
Theoretical weight of 12 suppositories without zinc oxide = 12 g
•
Cocoa butter displaced by 7.04 g of zinc oxide
= 12
−
10.56 =
1.44
•
Displacement value of zinc oxide
= (
7.04/1.44
) = 4.89
•
If 12 cocoa butter suppositories containing 40% zinc oxide weigh
17.6 grams,what is the displacement value of zinc oxide? Assume
that the suppositories are made in a 1-g mold
•
Given weight of 12 suppositories with zinc oxide = 17.6 grams
•
Weight of zinc oxide in the suppositories
=
(40/100)
×
17.6 = 7.04 g
•
Weight of cocoa butter in the suppositories
= (
60
/100)
×
17.6 = 10.56 g
•
Theoretical weight of 12 suppositories without zinc oxide = 12 g
•
Cocoa butter displaced by 7.04 g of zinc oxide
= 12
−
10.56 =
1.44
•
Displacement value of zinc oxide
= (
7.04/1.44
) = 4.89
9.
Weight and volume control
Various factors influence the weight of the
suppository, the volume of the suppository and
the amount of active ingredient in each
suppository are--
1.
Concentration of the drug in the mass
2.
Volume of the mould cavity
3.
The specific gravity of the base
4.
Volume variation between moulds
5.
Weight variation between suppositories due to
the inconsistencies in the manufacturing
process, The limit for the weight variation in
suppositories is 5%.
Weight and volume control
Various factors influence the weight of the
suppository, the volume of the suppository and
the amount of active ingredient in each
suppository are--
1.
Concentration of the drug in the mass
2.
Volume of the mould cavity
3.
The specific gravity of the base
4.
Volume variation between moulds
5.
Weight variation between suppositories due to
the inconsistencies in the manufacturing
process, The limit for the weight variation in
suppositories is 5%.
10.
Lubrication of moulds
•
Some widely used lubricating agents
are mineral oil, aqueous solution of
SLS, alcohol and tincture of green
soap. These are applied by wiping,
brushing or spraying
Lubrication of moulds
•
Some widely used lubricating agents
are mineral oil, aqueous solution of
SLS, alcohol and tincture of green
soap. These are applied by wiping,
brushing or spraying
11.
Rancidity
•
The unsaturated fatty acids in the
suppository bases undergo
autooxidation
and decompose into
aldehydes, ketones and acids. These
products have strong, unpleasant
odours
•
The
lower the content of
unsaturated fatty acids
in a base,
the higher is its
resistance
to rancidity
Rancidity
•
The unsaturated fatty acids in the
suppository bases undergo
autooxidation
and decompose into
aldehydes, ketones and acids. These
products have strong, unpleasant
odours
•
The
lower the content of
unsaturated fatty acids
in a base,
the higher is its
resistance
to rancidity
EVALUATION OF SUPPOSITORIES
Finished suppositories are routinely
inspected for; appearance & content
uniformity beside this--
•
Melting range test/micromelting range
•
Softning time (U tube water bath &
glass rod)
•
Drug release test
•
Breaking test (Fragility test)
•
Disintegration test
Finished suppositories are routinely
inspected for; appearance & content
uniformity beside this--
•
Melting range test/micromelting range
•
Softning time (U tube water bath &
glass rod)
•
Drug release test
•
Breaking test (Fragility test)
•
Disintegration test
•
Macro-melting range is a measure of
the
time it takes for the entire
suppository to melt
when immersed
in a constant-temperature (37
º
C)
water bath.USP tablet disintegration
apparatus is used
•
Micromelting
range for fat base using
capilllary tubes
•
ERWEKA
®
apparatus consist spiral
tube with thermostat water jacket.
91
Macro-melting range is a measure of
the
time it takes for the entire
suppository to melt
when immersed
in a constant-temperature (37
º
C)
water bath.USP tablet disintegration
apparatus is used
•
Micromelting
range for fat base using
capilllary tubes
•
ERWEKA
®
apparatus consist spiral
tube with thermostat water jacket.
91
Softening time
•
In this test a U tube is partially immersed in a
constant temperature bath and is maintained at a
temperature between 35 to 37
°
C.
•
There is a constriction in the tube in which the
suppository is kept
•
and above the suppository, a glass rod is kept.
•
The t
ime taken for the glass rod to go
through the suppository and reach the
constriction is known as or softening time
.
•
Another apparatus is there for finding
“
softening
time
”
which mimics in vivo conditions.
•
It uses a cellophane tube, and the temperature is
maintained by water circulation. Time taken for
the suppository to melt is noted
•
In this test a U tube is partially immersed in a
constant temperature bath and is maintained at a
temperature between 35 to 37
°
C.
•
There is a constriction in the tube in which the
suppository is kept
•
and above the suppository, a glass rod is kept.
•
The t
ime taken for the glass rod to go
through the suppository and reach the
constriction is known as or softening time
.
•
Another apparatus is there for finding
“
softening
time
”
which mimics in vivo conditions.
•
It uses a cellophane tube, and the temperature is
maintained by water circulation. Time taken for
the suppository to melt is noted
Breaking test
•
To measure the fragility or
brittleness of suppository
•
Double wall chamber in which the
test suppository is placed.
•
Water at 37
º
C is pumped through
the double wall.
•
The suppository supports a disc to
which rod is attached.
•
The other end of the rod consist of
another disc to which weights are
applied.
94
•
To measure the fragility or
brittleness of suppository
•
Double wall chamber in which the
test suppository is placed.
•
Water at 37
º
C is pumped through
the double wall.
•
The suppository supports a disc to
which rod is attached.
•
The other end of the rod consist of
another disc to which weights are
applied.
94
•
The test was conducted by placing the
suppository to support the axis of 600 g
weight.
•
At one minute intervals 200 gm weights
are added.
•
The weight at which the suppository
collapses is the breaking point
•
Different shape suppositories have
different value of hardness
.
95
Breaking test
The test was conducted by placing the
suppository to support the axis of 600 g
weight.
•
At one minute intervals 200 gm weights
are added.
•
The weight at which the suppository
collapses is the breaking point
•
Different shape suppositories have
different value of hardness
.
95
Breaking test
Dissolution/Disintegration test
•
In-vitro drug release pattern is measured by
using
ERWEKA
®
Disintegration
apparatus
•
Aliquots of the release medium were taken
at different time intervals within the melting
period.
•
The drug content in the aliquots was
determined using UV
•
The drug release pattern was plotted (time
versus-drug release curve)
•
In-vitro drug release pattern is measured by
using
ERWEKA
®
Disintegration
apparatus
•
Aliquots of the release medium were taken
at different time intervals within the melting
period.
•
The drug content in the aliquots was
determined using UV
•
The drug release pattern was plotted (time
versus-drug release curve)
Dissolution test apparatus
Packaging
•
Aluminium foil
•
Paper wrap
•
in-package moulding
•
Aluminium foil
•
Paper wrap
•
in-package moulding
Packaging of suppositories
•
They should not touch each other, otherwise they
may fuse togther
•
Proper wrapinng with aluminium foil, or paper is
required
•
Machine packaging avoid nonuniformity
–
after solidification wraping
–
sealing using two halves of plastic
•
In package moulding
–
Top of package mould remain open, after mass injected it
is sealed
–
High production rate
–
At high temperature shape is retained
•
They should not touch each other, otherwise they
may fuse togther
•
Proper wrapinng with aluminium foil, or paper is
required
•
Machine packaging avoid nonuniformity
–
after solidification wraping
–
sealing using two halves of plastic
•
In package moulding
–
Top of package mould remain open, after mass injected it
is sealed
–
High production rate
–
At high temperature shape is retained
Packaging, labelling & Storage for suppositories
Rigid paperboard
boxes
Flat box with a lid
Labelling :
1.
Store in a cool place
2.
For rectal use only
3.
Moisten before use (for glycero-gelatin and
macrogol bases)
Rigid paperboard
boxes
Flat box with a lid
Labelling :
1.
Store in a cool place
2.
For rectal use only
3.
Moisten before use (for glycero-gelatin and
macrogol bases)
Thank You
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