Transcript Suppositories-chapter-to-be-sent-to

Suppository Development and
Production
•
Marion Gold
Centerchem, Inc., Stamford, Connecticut.
•
Murti VePuri
Able Labs, South Plainfield, New Jersey
•
Lawrence H. Block
Duquesne University of, Pittsburgh,
Pennsylvania
1
Introduction

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Oral route of administration is the most
acceptable and common compared with other
routs of administration.
Oral route is not without limitations.
Some medication cause local stomach irritation.
Dose limitation.
Certain patients, children, elderly, and those with
swallowing problems, are difficult to treat with
oral tablets and capsules.
Target the medication to the affected area.
Ophthalmic, Nasal, Otic, Dermal, Vaginal
and Anorectal tissues.
2
Suppositories
The suppositories are the neglected dosage
form.
 Although lots of research done on this drug
delivery system, there are continues to be a
general rejection of the rectal delivery system.
 There are important reasons to consider
suppositories as a preferred route of
administration in many situation.

3
Why the rectal route?

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When the patient is unable to use the oral route
Through, unconsuous, irritation in the stomach
When the drug is less suited to oral administration
4
Definition
Solid or semisolid dosage forms used for rectal,
vaginal, or urethral administration of therapeutic
agents.
5
 Typically consist of dispersion of the active
ingredient in an inert matrix generally composed
of a rigid or semi-rigid base.
 This matrix should be inert not to interact with
the active ingredients and the excipients.
 The dispersed phase can be incorporated into
the suppository as:
 Solid (Powder).
 Liquid (either aqueous, alcoholic, or
glycolic solutions, oils, extracts, etc.
6

The material for the base, are selected on the bases of
its ability to soften, melt, or dissolve at body
temperature.

Finished suppositories are manufactured in a variety
of shapes and sizes to best suit the treatment
requirements (nature of the active ingredients, site of
administration.
Suppositories are available in
a range of physical forms
(molded or compressed,
foil or plastic wrapped, or gelatin
encapsulated.

7
Rectal administration & Applications
1.
2.
For local
Systemic drug delivery.
8
Drugs administered by rectal route
Local Effect
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Astringents.
Anti-septics.
Local anaesthetics.
Vasoconstrictors.
Anti-inflammatory.
Soothing agents.
Protective agents.
laxatives
Systemic Effect
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Analgesic &
antipyretic.
Anti-inflammatory.
Anti-asthmatic.
Anti-convulsant.
Anti-emetic.
Nausea
Narcotic analgesia
(Oxymorphone HCL)
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Advantages

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Reduce hepatic first-pass elimination
Enhance drug bioavailability.
Alcoholic and aqueous solution can be rapidly
absorbed, and this is used to considerable
advantage, for example, to administer diazepam
in the treatment of acute convulsive attacks.
10
Comparison with Oral Delivery


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Many studies have attempted to compare the
oral dosage form with the rectal administration.
The results are inadequate, because of the
different parameter used to make the studies, the
experiment conditions and choice of excipient.
Certain active ingredients are just not well suited
for suppository dosage.
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
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Diazepam (as an alcoholic solution &
propranolol have been shown to exhibit greater
bioavailability when administered rectally.
Theophylline suppositories was found
bioequivalence to oral administration when
microcrystalline drug was used.
Bioequivalence between pentobarbital despite its
slower rectal absorption.
In case where there is no first pass metabolism,
it has been shown that rectal administration of
drugs in solution can provide BE equivalent to
that seen with oral administration.
12
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
Absorption of the materials is via passive diffusion;
(no carrier-assisted means take part in the passage of
drug through lipid membrane).
Thus, success or failure of therapeutic delivery is a
function of lipo-solubility of the agent as well as its
vehicle, because the partition coefficient of the drug
between suppository base and the lumen contents
influences the latter's release into the bowel and
eventually the actives passage through the wall of
the intestine.
13

Enhancement agents that affect the mucous
membrane similarly affect absorption and are
useful for boosting delivery of poorly absorbed
agents such as antibiotics and high M.W
materials.
14
The use of suppositories in the world

Rectal as well as urethral and vaginal delivery of
drugs via suppositories makes excellent
therapeutic sense, and there use can be traced as
far back as in the writings of Hippocrates.

In Japan, rectal dosage forms are more
acceptable by the patient than other route of
administration.
More than 7.5% of all prescriptions in France
were formulation intended for rectal
administration.
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Anglo-Saxon countries, where social convention
preclude greater use of rectal delivery (generally
do not prescribe suppositories).
 Latin American and Mediterranean Europeans
use suppositories far more routinely.
In summary the use of rectal suppositories is
limited and are vary between nations.

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Factors affecting the absorption
from Rectal Suppositories
1.
2.
3.
Physiological factors.
Physicochemical factors of the drug substance.
Physicochemical factors of the base.
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1. Physiological Factors
1. Colonic content.
2. Circulation route.
3. pH, and lack of buffering capacity of the rectal
fluids.
1. When systemic effects are desired, greater
absorption may be expected from a rectum that
is void then from one that is distended with
fecal matter. An evacuant enema could be use
before the administration of a suppository.
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Physiological Factors continued
 Diarrhea, which case tissue dehydration of the
rectum can influence the absorption.
 Colonic obstruction due to tumorous growths,
influence the rate and the degree of drug
absorption from the rectal site.
2. Circulation Route, drugs absorbed rectally,
bypass the portal circulation during their first
pass into the general circulation
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
3. pH and lack of buffering capacity of the
rectal fluids.
The rectal fluids are neutral in pH (7-8), and
have no effective buffering capacity.

The drug is administered will not generally be
chemically changed by the rectal environment.

The suppository base used has major influence
on the release of active constituents
incorporated into it.
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Physicochemical Factors
Includes:
1. Solubility of the drug in lipid and in water.
2. Particle size of dispersed drugs.
3. Physicochemical factors of the base include its
ability to:
 Melt.
 Soften.
 Dissolve at body temperature.
 Release the drug substance,
 and its hydrophilic or hydrophobic character.
21

Lipid-water solubility:
The lipid-water partition coefficient of a drug is an
important factor in the selection of the suppository
base and in 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 the hydrophilic substance presents in a
fatty base.

Water soluble base such as, PEG, which dissolve in
the anorectal fluids, release for absorption both
water soluble and oil soluble drugs.
22
Physicochemical Factors Continue…
Particle size:
Particle size of drugs present in the suppository
in the undisclosed stat, the smaller the particle
size the more readily the dissolution of the
particles and the greater the chance for rapid
absorption.
Nature of the base:
Melting point, softening, or dissolving to release
its drug components for absorption, interacting
with the drugs substance.
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Ratio of Components

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Once the correct excipient has been selected, the
proper proportion of the components needs to
be established.
One important aspect to consider in suppository
formulation is that of displacement.
Suppositories generally weigh between 1 to 4 g,
and displacement of the excipient by the active
ingredient must be calculated when the product
is formulated.
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
Simply, this step takes into account the volume
of suppository base that will be displaced by an
insoluble drug dispersed into it.

This is necessitated by the practice of placing
weighed quantities of suppository ingredients
into molds whose contents are measured
volumetrically.
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M = F - (f * S)
M = the quantity (weight) of suppository base needed.
F = the total capacity of the suppository mold.
f = the displacement factor of the active ingredients.
S = the quantity of the active ingredient per
suppository.
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Calculation of Displacement
Value
M = the quantity (weight) of suppository base needed.
F = the total capacity of the suppository mold.
f = the displacement factor of the active ingredients.
S = the quantity of the active ingredient per
suppository.
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Displacement Value
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The volume of a suppository from a particular mould is
uniform.
The weight is vary according to the density of the
medicaments.
The displacement value of a drug is the number of
parts by weight of drug which displaces one part by
weight of the base.
Could be calculated and could be found in the literature.
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Displacement Factors of Selected Materials
Acetylmorphine Hydrochloride
0.71
Acetylsalicylic acid
0.63
Beeswax
1.0
Benzocaine
0.68
Bismuth subgallate
0.37
Bismuth sbnitrate 0.33
0.33
Codeine phosphate
0.8
Glycerin
0.78
Phenacetin
0.6
Phenobarbital
0.84
Phenobarbital sodium
0.62
Procaine
0.8
Quinine chlorohdrate
0.83
Sulfamide
0.6
Theophylline
0.63
Zinc oxide
0.2
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Formulation
OK
A. Choice of drug:
What makes a particular drug a candidate for
administration in the form of a suppository?
1) It must be sufficiently absorbed through the
rectal mucosa to permit therapeutic blood levels.
2) Drug that are poorly absorbed after oral dosage.
3) Drugs that cause irritation to the gastrointestinal
mucosa.
4) Certain antibiotics cause major changes to the
balance of intestinal flora, and there would be
better given as suppositories.
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5) Small polypeptides-normally subject to the
enzymatic activity of the upper GIT, can often be
OK
better administered via the rectum.
6) The pH of the upper GIT causes inadequate or
otherwise undesirable uptake.
7) For local conditions achieved using a suitable
suppository formulation.
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1.
NO
Nature of the active.
Three principal factors that define formulation
requirements:
1.
2.
3.
The actives physical state under
ambient conditions.
The solubility characteristics of the
active.
The physicochemical activity with
regards to potential excipients.
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1. Physical State.



NO
The active can be either liquid, pasty, or solid in
nature.
Bulk Density. the big difference in the density
between the active and the base cause problem
during filling and homogeneity of the
suppositories.
Solubility:
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B. Choice of the Base
NO
1) They enable a selected active to be fabricated in
a manner appropriate to both its
physicochemical characteristics and the
requirements of the manufacturer.
2) They are used to control delivery of the
medication at its site of absorption.
3) For this reason the bases manufacturers offer a
wide selection of raw materials in order to
anticipate a correspondingly broad range of
product needs.
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Selection criteria of the baseNO
A.
Nature of the active ingredient.
B.
Manufacturing capabilities.
C.
Desired release characteristics.
D.
Chemical no-reactivity with the active.
E.
Nontoxic and nonirritant, and stable when
formulated.
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Selection of the appropriate Base
NO
I.
During Production:
 Slight
contraction upon cooling in order to
facilitate removal from the mold.
 Inertness no chemical interaction between the
base and the active ingredients.
 Solidification (should be optimum).
 Viscosity: to be viscose to prevent
sedimentation during filling until cooling.
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II.
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During Storage:
NO
Impurity.
Bacterial/Fungal contamination should be
minimized by selecting a non-nutritive
base with minimal water content.
Softening.
The suppositories should be formulated so
that it does not soften or melt under
transportation and storage conditions.
Stability.
The selected materials can not oxidize
when exposed to air, humidity, Or light.
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III.
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During Use:
NO
Release.
Choice of the proper base provides optimal
delivery of the dispersed active into the
target site.
Tolerance.
The finished suppository should have
minimal toxicity and not be irritating to
sensitive rectal mucosal tissue.
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Suppository Basis
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
Suppository bases plays an important role in the
release of the drug they hold and therefore in the
availability of the drug for absorption for systemic
effects or for local action.
And because of the possibility of chemical and or
physical interactions between the drug and the
base, which could affect the stability and or
bioavailability of the drug, the absence of any drug
interaction between the two agents should be
ascertained before formulation
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Suppository Bases

From the point of view of composition,
suppository bases can be described as falling
into one of the three categories:
1. Naturally derived.
2. Synthetic.
3. Semisynthetic.
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I. Natural Bases
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All naturally derived suppository bases used
today are produces from Cocoa Butter, it’s a
fatty material composed of a mixture of C16 to
C18 saturated and unsaturated fatty acid
triglycerides obtained from the roasted seed of
Theobroma cacao.
Fatty bases are the most frequently used
suppository bases.
These bases melt at body temperature.
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 In addition to cocoa butter, other natural
materials such as:
 Gelatin, Agar, and Waxes have been employed
as suppository bases.
 Their uses are limited and often relegated to
special applications because special problems are
encountered with their use.
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Advantages:
1. It is readily liquefies on heating but sets rapidly
when cooled down.
2. Melt at body temperature.
3. It is miscible with many ingredients.
4. It is bland, therefore no irritation occurs.
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Disadvantages:
Despite Theobroma oil been used for over 200
years, however it is not without limitations.
And those limitations are:
1. Theobroma oil is polymorphic i.e. when it is
heated and cooled it solidifies in a different
crystalline form.
2. Theobroma oil shrinks slightly on cooling,
adherence to the walls of suppository mold.
3. The relatively low melting point makes it
unsuitable for use in hot climates.
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4. The melting point is reduced if the active ingredients
are soluble in the base.
5. Theobroma oil deteriorates on storage and is prone to
oxidation.
6. The quality of Theobroma oil may vary from batch to
batch, and it can be expensive.
For these reasons, the use of cocoa butter as a
suppository base is becoming increasingly less
attractive, particularly in the of the availability of
more modern alternatives.
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II. Synthetic & Semi-synthetic Bases


Chemically they are usually derivatives of fatty
acids that undergo chemical alteration
(transesterification) to enhance their use for this
application
Such chemical reactions yield a range of
products with controllable characteristics making
them suitable to be used as suppository bases.
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For example:



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Hydrogenation is typically carried out to improve
stability (enhance stability to oxidation and to
increase chemical inertness).
Hydrogenating suitable vegetable oils such as
(Palm kernel oil and cottonseed oil) are used.
Melting point ranges can be more precisely
tailored to specific requirements.
Examples of semisynthetic suppository bases:
Novata, Suppocire, Wecobee and Witepsol
types.
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Advantages:

The base is more flexible and not brittle.

More stable on oxidation and hydrolysis.

Less irritant compare with other bases.
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Disadvantages
1. The viscosity of the synthetic fats, when
2.
3.
4.
5.
melted, is lower than that of Theobroma oil.
this may lead to.
Sedimentation risk of the active ingredients
during the preparation process.
Lack of uniformity of the active ingredients.
These bases become very brittle if cooled too
rapidly, so should not be refrigerated during
the preparation period.
There is more than one grade of synthetic fatty
basis.
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Water soluble & water miscible bases
1. Glycerol-gelatin bases:




These bases is a mixture of glycerol and water, which is
stiffened with gelatin.
Mass of Glycerol suppositories BP has 14% w/w gelatin
and 70% w/w glycerol.
In hot climates gelatin content can be increased to 18%.
Gelatin is purified protein produces by the hydrolysis of
the caliginous tissue of animals such as skins and bones.
There is two types of gelatin: Type A
and Type B.
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This type of base is less frequently used than the
fatty bases for a variety of reasons.
Disadvantages of this type of bases:
1.
Glycerol-gelatin base have a physiological effect.
This is useful if a laxative effect is required but
otherwise is undesirable.
2. Difficulties in preparation and handling.
3. The dissolution time depends on the content and quality
of the gelatin and also the age of the suppository.
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4. They are hygroscopic and therefore require
careful storage and may cause rectal irritation.
5. Possibility of microbial contamination is more
likely than with the fatty bases.
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2. Macrogols



These are different types of polyethylene glycols
which are blended together to produce suppository
bases which vary in:
 Melting point.

Dissolution rates.

Physicochemical characteristics.
High polymer produce preparation which release the
drug slowly (they are brittle).
A combination of different polymer release the drug
more readily can be prepared by mixing high
polymers with medium and low polymers. (Less
brittle)
53
Drug is release as the base dissolves in the
rectal contents.
Advantages:
1.
2.
3.
4.
5.
They have no physiological effect, e.g. do not produce a
laxative effect.
They are not prone to microbial contamination.
Some polymers have a high melting point.
They have a high water-absorbing capacity.
In solution, viscosity is high, which means there is less
likelihood of leakage from body.
54
Disadvantages:
1. They are hygroscopic which means they must
be carefully stored.
2. They are incompatible with several drugs and
materials, e.g. bnzocaine, penicillin and plastic.
3. They become brittle if cooled too quickly and
also may become brittle on storage.
4. Crystal growth occurs with some active
ingredients.
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Hydrogels




Currently, an alternative vehicle for rectal delivery is
being actively investigated.
Hydrogels are among them, and it defined as
macromolecular networks that swell, but do not
dissolve, in water.
The swelling of hydrogels, i.e., the absorption of
water, is a consequence of the presence of
hydrophilic functional groups attached to the
polymeric network.
The aqueous insolubility of hydrogels results from
the cross-links between adjacent macromolecules.
56

The use of hydrogel matrix for drug delivery
involves the dispersal of the drug in the matrix,
followed by drying of the system and
simultaneous immobilization of the drug.

When the hydrogel delivery system is placed in
an aqueous environment, e.g., the rectum, the
hydrogel swells, and drug is then able to diffuse
out of the macromolecular network.
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Selection Criteria

Melting Temperature Range.

Iodine Value.
Hydroxyl Index.

58
Suppository Production Methods
1. Melting.
2. Compression.
3. Injection.
 Injection molding production process involving
PEGs as the base might proceed as follows:
 The PEGs are first melted and mixed in a vessel
equipped with a stirrer and a heating device at
about 60°C to 80°C .
59



Additional viscosity -plasticity –adjusting
ingredient, auxiliary ingredients, and actives are
added while stirring.
Once blending is complete, the melt is extruded
into precision-machined multi-cavity molds.
Rapid solidification of the melt is followed by
ejection of the molded units from the mold
cavities.
Very fast,
 Precise metering and molding.
 Range of shapes and sizes

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In-Process Control


Proper monitoring of product physical
characteristics is necessary to ensure that the
production process remains under control
throughout filling.
Visual Examination: Examination of physical
defects of finished suppositories provides
valuable information for process monitoring.
Color variations, chips, cracks, depressions, and
surface irregularities are evidence of problems
that require attention.
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1)
Weight checks: periodic weighing of individual
suppositories will reveal problem in the filling
operation. (in each filling needle).
2)
Leak Test
3)
The quality of the seal is a parameter that can
affect the stability of the product (vacuum test).
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Quality Control
A. Physical Analysis:
1.
Visual Evaluation, surface appearance and
color can be verified visually to assess:

Absence of fissuring, pitting, fat blooming,
exudation, and migration of the active ingredients.
The last test accomplished by taking a longitudinal
section of the suppository to verify the
homogeneity of the active ingredients within the
mass.
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2. Melting Point.
The melting point is a critical factor in the
determination of the release rate of the active
ingredients from the suppository.
 The melting point of the finished suppository
should generally; not be greater than 37°C.
64
3. Liquefaction Time.



This is an important element indicates the
physical behavior of a suppository subjected to
its maximum functional temperature 37°C.
It measures the time necessary for a suppository
to liquefy under pressures similar to those found
in the rectum (30g) in the presence of water at
body temperature.
A rule of thumb is that liquefaction time should
be no longer than 30 minutes.
65
4. Mechanical strength:
This is the determination of the mechanical
force necessary to break a suppository, and it
indicates whether a suppository is brittle or elastic.
 The mechanical strength should in no case be
less than 1.8 to 2 kg.
66
5. Melting and Solidification:
The most commonly used methods are:
 Open capillary tube.
 U-Tube.
 Drop Point.
 These methods are similar in principle, differ
somewhat in their methodologies. all require the
introduction of a sample into a specified place in
the apparatus, after which heat is applied in a
controlled manner.
 Means are provided for the determination of the
point at which the test material undergoes a change
in physical state, (i.e., melts).
67
1.
2.
3.
4.
5.
6.
7.
8.
9.
An ideal suppository base must:
Melt at or just below body temperature or
dissolve in body temperature.
Solidify quickly after melting.
Be miscible with many ingredients.
Be bland, i.e. non-toxic and non-irritant.
Be stable on storage.
Be resistant to handling.
Be stable to heating above its melting point.
Release the active ingredients readily.
Be easily molded and removed from the mold.
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Release Process of drug from
suspension suppository

Suppository

Melting and Spreading

Sedimentation

Wetting

Dissolution
69
Factors affecting drug release
process

Temperature

Contact area

Release medium

Movements

Membranes
70
Formulation of suppositories





Different types – rectal, vaginal, and urethral.
Different shapes and sizes
Usually between 1-4g
Drug content varies widely – 0.1% to 40%
Vehicle (base) in which drug is incorporated –
sometimes contain other additives
71
Mould Calibration



The capacity of the mould is determined by
filling the mould by the chosen base.
The total weight of the perfect product is taken
and a mean weight calculated.
This value is the calibration value of the mould
for the particular base.
72
7.
8.
9.
10.
11.
12.
13.
14.
15.
Melt 2/3 of the base and then remove form the heat,
the residual heat will melt the rest of the base.
Reduce the particle size of the active ingredients.
Weigh the correct amount of medicament and place
on a glass tile.
Add half of the molten base to the powdered drug and
rub together with a spatula.
Scrape this mixture off the tile, using the spatula and
place back into the porcelain basin.
Quickly pour into the mould, slightly overfilling each
cavity.
Leave the mould and its contents to cool for 5 min.
Allow to cool for further 10-15 min.
Unscrew the mould and remove the suppositories.
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Packaging and Storage





Plastic (PVC) or aluminium foil pack
Protection against moisture and oxygen
Store in cool place
High humidity – absorb moisture – spongy
Low humidity – lose moisture - brittle
74