2. What Is A Suppository?What Is A Suppository?
A suppository is a medicated solid dosage
form used in the rectum, vagina and urethra.
Suppositories often contain vehicles that
melt or soften at body temperature.
Vaginal suppositories, called pessaries, can
be made as compressed tablets.
Urethra suppositories are called bougies.
3. Shapes and Weights ofShapes and Weights of
SuppositoriesSuppositories
Rectal suppositories weigh about 2 grams for
adults and 1 gram for children. They are bullet
shaped.
Vaginal suppositories weigh about 3 to 5 grams
and are oval or globular shaped.
Urethral suppositories for males weigh about 4
grams & are 100-150 mm long. Female urethral
suppositories weigh about 2 grams and are 60-
75mm in length. They are pencil shaped and
pointed on one end.
5. Types of Suppository BasesTypes of Suppository Bases
Oleaginous (i.e. triglycerides)
Lipid based suppositories are typically used for hemorrhoidal
preparations but can be used for vaginal and urethral dosing.
Glycerinated Gelatin
Used particularly for vaginal suppositories. They are a translucent
gelatinous solid that tend to disperse slowly in mucous secretions
to provide prolonged release of active ingredients.
Polyethylene Glycol (PEG) polymers
PEG based suppositories offer rapid delivery of the API with
minimal manufacturing issues.
Surfactants
Surfactant based suppositories offer rapid delivery but cannot be
used for an extended period of time because of irritation.
Tablets
Used particularly for vaginal suppositories.
6. TriglyceridesTriglycerides
A triglyceride is a lipid with a glycerin
backbone with three fatty acid groups
A molecule of glycerin can be pictured as a
capital E. It becomes a glyceride when one of
the “forks” becomes attached to a fatty acid. If
all the forks contain fatty acid groups, the
result is a triglyceride.
Cocoa butter (theobroma oil) and most
suppository bases intended for hemorrhoid
therapy are triglycerides.
7. Crystallization and Melting RangesCrystallization and Melting Ranges
of Cocoa Butterof Cocoa Butter
Cocoa butter is a polymorphic substance.
There are four to six forms of crystals in
cocoa butter.
Different researchers have used different
nomenclatures over the years.
Different researchers disagree over the
number of crystal forms.
8. Crystal Melting Ranges of Cocoa ButterCrystal Melting Ranges of Cocoa Butter
VAECK
(1960)
DUCK
(1964)
WILLIE & LOVEGREN
(1966)
LOVEGREN ET. AL
(1976)
DAVIS & DIMICK
(1986)
Form Temperature Form Temperature Form Temperature Form Temperature Form Temperature
γ 17 γ 18 I 17.3 VI 13.0 I 13.1/17.6
ά 21-24 ά 23.5 II 23.3 V 20.0 II 17.7/19.9
III 25.5 IV 23.0 III 22.4/24.5
β' 28 β'’ 28.0 IV 27.3 III 25.0 IV 26.4/27.9
β' 33.0 V 33.8 II 30.0 V 30.7/34.4
β 34-35 β 34.4 VI 36.3 I 33.5 VI 33.8/34.1
9. Tempering Cocoa ButterTempering Cocoa Butter
Tempering is a process that puts desired
crystal structure in cocoa butter.
Tempering improves product stability.
Poor tempering results in a poor product
with marginal overall aesthetics.
10. The Tempering ProcessThe Tempering Process
Melt the cocoa butter completely at 50-52ºC (eliminates crystal
memory)
Cool the cocoa butter with mixing to 25ºC. (mitigates the
formation of Form I, II and III crystals).
Continue to mix at this temperature product until the viscosity is
at a maximum (maximum crystal growth of Form IV, V and VI).
Heat the product to 33-35ºC with continued mixing (Form V
predominates).
Form into suppositories
11. Synthetic Fatty BasesSynthetic Fatty Bases
Most if not all triglycerides (including
synthetic triglycerides) go through a
phase transition. Typically, it is the form
V to VI. Some manufacturers insist that
Span 65 be used to stabilize the
formulation. Regardless, post hardening
of the suppository is an issue and must be
addressed during formulation.
12. Fat BloomFat Bloom
Fat bloom is recognized as a grayish
white film on the surface.
Fat bloom is occurs because fat migrates
to the surface through micro-fissures and
crystallizes as “bloom.”
Fat bloom is an aesthetic issue and does
not have an impact on product quality.
13. Causes of Fat BloomCauses of Fat Bloom
Poor tempering
Bloom can form if cocoa butter is mixed
with incompatible fats
High moisture
14. Surfactant Use Inhibits Fat BloomSurfactant Use Inhibits Fat Bloom
The mechanism is as follows:
The IV to V transition is facilitated because
this transition occurs in the liquid phase
only.
The V to VI transition is hindered because
there is less solid fraction in the butter and
this transition occurs only in the solid
phase.
16. Surfactants as BioavailabilitySurfactants as Bioavailability
EnhancersEnhancers
Cleansing action caused by the surfactant-
containing vehicle may make additional pore
spaces available for drug absorption.
Drug movement across the rectal
membrane is facilitated.
17. DrawbacksDrawbacks
of Surfactant Use in Suppositoriesof Surfactant Use in Suppositories
Absorption is decreased for phenol type
drugs, likely due to drug surfactant
complex
Surfactants can disrupt mucosal
membrane and produce a marked
histological change to the mucosa after
prolonged administration.
18. Insoluble APIsInsoluble APIs
It is difficult to suspend insoluble APIs
while forming suppositories.
Content uniformity is a challenge. Some
commonly used APIs (i.e. phenylephrine
HCl) are present at 0.15%.
Possible formulation strategies include
solubilizing the API and spraying it onto
starch (or other carrier)
19. Soluble APIsSoluble APIs
Water soluble, oil insoluble salts are
preferred in fat based suppositories.
If the drug has a lipid-water coefficient
favoring fat solubility, the drug will be
released slowly if at all.
20. Water Soluble BasesWater Soluble Bases
Ideally, water soluble bases should be
used whenever possible.
Typical water soluble bases are
glycerinated gelatin and PEG
21. Suppository TabletsSuppository Tablets
Typically used for vaginal dosing
Ingredients include API, lactose and /or
dextrose, boric and/or phosphoric acid to
adjust acidity of the vagina to pH 5.
Vaginal tablet suppositories are used for
topical therapy.
22. Drug Absorption From OralDrug Absorption From Oral
AdministrationAdministration
Drug is absorbed from the small intestine
and is carried to by the hepatic portal
vein to the liver.
Therapeutic activity may be modified by
the liver.
Systemic effectiveness may be affected
because the liver chemically modifies
many drugs after absorption.
23. Drug Absorption From RectalDrug Absorption From Rectal
SuppositoriesSuppositories
Drug absorption by the hemorrhoidal veins
surrounding the colon and rectum enter into
the inferior vena cava and by-pass the liver.
The upper hemorrhoidal vein does connect
with portal veins leading to the liver.
The rate limiting step is the diffusion of the
drug to the site of the drug to the site of the
rectal mucosa at which absorption occurs.
24. ConclusionsConclusions
Suppository formulations using cocoa
butter (or synthetics) requires detailed
knowledge of the raw materials used to
manufacture suppositories.
Suppository formulation using water
soluble bases are the ideal and are
preferred.
Drug absorption is dependent on many
factors such as pH , drug solubility and
suppository vehicle.
Editor's Notes
From Lachman et.al , “The word suppositories is derived from the Latin word suppositorium and was first used to designate this medicinal form about the seventeenth century.”
Tween 61, Myrj 51, etc.
Not enough colonic fluid to dissolve a tablet.
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 and thus may be safely stored at room temperature.
If one fatty acid is attached it is a monoglyceride. If two fatty acid molecules are attached it is a diglyceride. If three are attached it is a triglyceride. Most naturally occurring lipids are triglycerides.
If the crystal structure is not properly managed while manufacturing cocoa butter the resulting product will not harden in a reasonable amount of time or there may be post-hardening issues or considerable fat bloom.
Gamma only forms at temperatures under 17 C
Alpha forms only from gamma is present at temperatures up to 24 C
Beta prime forms at temperatures above 24 C. It also forms from alpha crystals. If product does not go below 24 C only beta can form.
Eventually everything goes to beta
Poor tempering results in poor product
Microscopic cracks can occur
Moisture transfer in or out of the suppository
Micro-fissures allow crystal migration (fat bloom)
Creates a dull surface.
Use examples of fat bloom and poor temper.
All steps of the tempering process are critical.
Milk fat also inhibits bloom.
The IV to V transition occurs in the liquid phase only. Since the liquid phase is increased by the addition of the surfactant, this allows the transition to occur readily.
The V to VI transition is hindered because there is less solid fraction due to the surfactant.
Use of a surfactant causes the resulting suppository to become softer. This is because the liquid fraction is increased.
That is why milk chocolate is softer than dark chocolate.
Examples are: Aspirin, Oxymorphone HCl.
Most OTC suppositories manufactured in the US are for hemorrhoidal preparations. For this application, a fatty base is an integral part of the therapy.
The liver chemically modifies many drugs after absorption.
More than half of rectally administered drugs are absorbed directly into the general circulation. The lymphatic circulation helps in absorbing the drug and diverts it from the liver.
From 1…and the API and its uptake by the circulatory system.
From 2…pH is a major factor.
