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Suppositories

Ideal requirements,
Bases,
Manufacturing procedure,
Packaging and
Evaluation.

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Introduction

• A suppository is a drug delivery system that is


inserted either into the rectum (rectal
suppository), vagina (vaginal suppository) or
urethra (urethral suppository) where it
dissolves.

• 1. Active ingredient + 2. Base + 3. Additives

• Oval, Bullet and Torpedo Shape


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Advantages of Suppositories
• Self administration

• Avoidance of oral and parenteral routes


– Avoid first pass metabolism
– Protect drug from harsh conditions in stomach
– Drug causes nausea and vomiting
– Oral intake restricted before surgery

• Patient suffering from severe vomiting

• Can be targeted delivery system


– Localized action reduced systemic distribution
– Rectum vagina & urethra poor blood flow
• Get to site of action with lower dose
• Reducing systemic toxicity
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Disadvantages of Suppositories
• Mucosal irritation
– Eg: indomethacin can cause rashes

• Patient non-compliance

• Erratic and undesired absorption


– Placement too high -> first pass metabolism
– Installation may trigger defecation reaction
• expel product

• GI state affects absorption


– Diarrhea & disease states affect absorption
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Disadvantages of Suppositories
• May get absorption when don't want
– e.g. Estrogen creams

• ⇑ absorbed into circulation ⇑ Side effects

• High cost of manufacture


– Special formulation
– Special packaging

• Lack of comparative data


– Not well researched area
– Company avoid financial risk

• Can melt at ambient temperatures


– e.g., Baltimore in the summer
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Rectal suppositories
• Rectal suppositories are commonly used for:
• For laxative purposes, with chemicals such as glycerin or
bisacodyl.
• To treat a hemorrhoid by delivering a moisturizer or
vasoconstrictor.
• Delivery of many other systemically-acting medications, such as
promethazine or aspirin.
• For general medical administration purposes: the substance
crosses the rectal mucosa into the bloodstream; examples
include paracetamol (acetaminophen), diclofenac, opiates, and
eucalyptol suppositories.
• Bullet and Torpedo Shape
• For Local / Systemic action
– 4 gm adult
– 1 gm child

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Vaginal suppositories
• Vaginal suppositories are commonly used to treat
gynecological ailments, including vaginal infections such as
candidiasis.

• Round or Oval Shape

• 3-4 g, D. 12 mm, L. 33-35 mm

• Local action eg. antibacterial (Trichomonas spp.),


contraceptive, anti-fungal

• Vaginal tablet : Wet granulation production used water


soluble diluent (lactose)

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Vaginal suppositories Example
• Progesterone vaginal suppositories
– F < 10%
• Poor absorption and high 1st pass metabolism
• Lessen the possibility of miscarriage
– luteal phase defect
– In vitro fertilization (IVF) -> uterine lining development

• NPO – preoperative maintenance therapy


– Aminophylline / theophylline Suppositories

• Miconazole Vaginal Suppositories


– Fungus resides on mucosal membranes
– i.e., outside the body, need high PO dose

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Urethral Suppository
• Urethral therapy is one of several
proven treatment options for ED. The
therapy treats impotence by delivering
medication directly to the penis to
stimulate blood flow. The medication is
in the form of a small suppository.
• Alprostadil pellets are urethral
suppositories used for the treatment of
severe erectile dysfunction. They are
marketed under the name Muse in the
United State.
• Directly inserted into the penis, the
suppository is absorbed by the tissue
and relaxes muscles in the penis. This
allows blood flow to increase, creating
an erection.
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Suppository Bases
Ideal base
• Melts, dissolves, or disperses at 37oC
• Nonirritating
• Physically stable -> manufacture & storage
• Chemically stable & inert
– No color change
– Compatible with drugs
• Convenient to handle -> break or melt
• High viscosity when melted
– Doesn't leak from rectum or vagina

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Base Classification
• Oleaginous
– Cocoa-butter
– Cocoa-butter substitutes
• Water soluble (Hydrophilic Bases)
– Polyethylene - glycol mixtures
– Glycerated gelatin
• Water dispersible
– Polyethylene-glycol derivations
– Cocoa-butter substitutes with surfactants
• Non-base
– Tablets
– Soft gelatin capsules

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Drug Release
• Oleaginous

• Hydrophilic

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Cocoa-butter (Theobroma oil)
• Most widely used base for Rx
– Innocuous
– Bland
– Nonreactive
– Melts at body temperature

• Disadvantages
– Fatty acids can become rancid
– Melt in warm weather
– Liquefy when certain drugs are incorporated
– Variable properties (natural product)
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Cocoa-butter Composition
• Obtained from roasted seed of Theobroma Cacao
• Primarily triglyceride
– Oleopalmitostearin
– Oleodistearin
• Yellowish-white solid
• Brittle fat
• Smells and tastes like chocolate
– Melting point 30-35 0C
• Stored in cool, dry, light protected

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Cocoa-butter: Polymorphic properties

• polymorphism and rancidity when Heat


• 4 forms of theobroma crytal
1. beta crystal (mp 34-36oC)
2. beta’ crystal* (mp 27oC)
3. alpha crystal* (mp 22oC)
4. gamma crystal* (mp 18oC)

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Cocoa Butter Substitutes
• Cocoa butter is bad for high speed manufacture
• Cocoa butter replacements
– Mixtures of synthetic or natural vegetable oils
– Triglycerides of natural saturated fatty acids
– Wax
– Fatty alcohols C10- C18
• e.g. Cotmar, Dehydag, Wecobee, Witepsol & Fatty
base

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Hydrophilic: Glycerinated Gelatin
• Glycerinated Gelatin
– Mixture glycerin and gelatin
• Ratio glycerin/gelatin/H2O -> duration of action
– Oldest type
• Example
– USP 24
• Purified H2O 10 gm
• Glycerin 70 gm
• Gelatin 20 gm
• Vaginal suppositories (Above Rx used for)
– Local application of antimicrobials
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Glycerinated Gelatin Cont.
• Glycerin hygroscopic protect from H2O
– Patient counseling leave in package
• Will support mold and bacterial growth
• Can use preservative
– Propylparaben 0.02% & Methylparaben 0.18%

• Not as good for rectal delivery


– Absorb H2O from mucosal membranes
– Wet before use to:
• Avoid/reduce “stinging”
• Faster dissolution
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Hydrophilic Bases PEG
• Polyethylene glycols
– HOCH2(CH2-O-CH2)nCH2OH
– Properties change with MW
– Liquid 200-600 MW
– Wax-like solids . MW > 1000
• Will not support mold growth
• Packaged in tightly closed containers
– Absorbs H20.
– Can store without refrigeration
• Labeling
– Moistened with water before inserting
– Avoid/reduce “stinging”
– Faster dissolution
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PEG Cont.
Example
Base 1 Base 2
• PEG-1000 96% 75%
• PEG-4000 4% 25%
• Base 1
– Low melting (refrigerate in summer)
– Rapid drug release
• Base 2
– Higher melting
– Slower drug release
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Compressed Tablets
• Not common for rectal suppositories
– Low moisture environment
• Advantages
– Becoming more popular for vaginal use
– Easier to manufacture
– More stable
• Heat storage & chemical reaction
– Doesn't melt and run out

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Base Selection
• Vehicle influences drug release!
– Cocoa butter immiscible with body fluids
• Inhibits diffusion of fat-soluble drugs
• Ionized drugs partition more readily
– Water-miscible bases
• Can dissolve very slowly -> retarding release

• Systemic absorption
– Generally:
• Ionized ⇑ bioavailability
• Nonionized ⇓ bioavailability
• e.g., Codeine phosphate or sulfate is better in cocoa butter than
Codeine
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Base Selection Cont.
• Oleaginous vehicles
– Less irritation of rectum
– Less popular in vaginal preparations
• Nonabsorbable residue

• Hydrophilic vehicles
– Less popular rectally
– Slow dissolution
– Vehicle -> relatively slowly cleared vaginally
• Less likely to leak (where no sphincter muscles)

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Base Selection Cont.
• Chemical Stability
– Fatty Bases > PEG

• Some drugs lower melting point


– Volatile oils, creosote, phenol, chloral hydrate
– White wax or cetyl ester raises T-melt
• Note too much wax
• T-melts > 37 oC

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Base Selection Cont.
• Cocoa butter has no emulsifier
– Low water uptake 20-30 gm H2O/100 gm
– Tween 61 5-10% increases water absorption

• Hydrophilic drugs can precipitate


– Tween 61 helps solubilize hydrophilic drugs

• Surfactants
– ⇑ bioavailability
• Breakup suppository -> faster release
• Disperse drug better
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Preparation of Suppositories
• Cold Process
– Hand rolling used with Cocoa Butter base
– Compression mold used with Cocoa butter base &
PEG base

• Hot Process / Fusion


– Soluble drugs
– Insoluble drugs

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Manufacturing of Suppositories
• Four Methods are used in preparing
suppositories
1. Molding by Hands
2. Compression Molding
3. Pour Molding
4. Automatic Molding Machine

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Density (Dose Replacement)
Calculations for suppositories
• The density factors of various bases & drugs need to be known to
determine the proper weights of the ingredients to be used.
• Density factors relative to cocoa butter have been determined.
• If the density factor of a base is not known, it is simply calculated as
the ratio of the blank weight of the base & cocoa butter.
• Three methods of calculating the quantity of base that the active
medication will occupy & the quantities of ingredients required
are:-
– Determination of the dosage replacement factor
– Determination of density factor method
– Determination of occupied volume method

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Determination of the dosage
replacement factor

Where
E= the weight of the pure base suppositories
G= the weight of suppositories with X% of the active ingredient.

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Determination of density factor
method

Where
A= Average weight of blank
B= Weight of medication per suppository
C= Average weight of medicated suppository

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Determination of density factor method
contd…..
1. Determine the average blank weight, (A), per mold using the suppository base
of interest.
2. Weigh the quantity of suppository base necessary for 10 suppositories.
3. Weigh 1 g of medication. The weight of medication per suppository, (B), is
equal to 1g/10 suppositories = 0.1 g / Suppository.
4. Melt the suppository base & incorporate the medication, mix, pour into
molds, cool, trim, & remove from the molds.
5. Weigh the 10 suppositories & determine the average weight (C)

6. Take the weight of the medication required for each suppository & divide by
the density factor of the medication to find the replacement value of the
suppository base.
7. Subtract this quantity from the blank suppository weight.
8. Multiply by the number of suppositories required to obtain the quantity of
base required for prescription.
9. Multiply the weight of drug per suppository by the number of suppositories
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active drug required for the prescription.
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Determination of density factor method
Example
• Prepare 12 acetoaminophen 300 mg suppositories using cocoa butter. The
average weight of the cocoa butter blank is 2g & the average weight of
medicated suppository is 1.8g.

• From step 6). (0.3g)/0.6 = 0.5 (Replacement value of the base)


• From step 7). 2.0g – 0.5g = 1.5 g
• From step 8). 12 x 1.5 g = 18 g cocoa butter required
• From step 9). 12x0.3g = 3.6 g acetaminophen
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Determination of occupied volume method
1. Determine the average weight per mold (blank) using the
designated base
2. Weigh out enough base for 10 suppositories.
3. Divide the density of the active drug by the density of the base to
obtain a ratio.
4. Divide the total weight of active drug required for the total
number of suppositories by the ration obtained in step 3. This will
give the amount of base displaced by the active drug.
5. Subtract the amount obtained in step 4 from the total weight of
the prescription (number of suppositories multiplied by weight of
the blanks) to obtain the weight of base required
6. Multiply the weight of active drug per suppository times the
number of suppositories to be prepared to obtain the quantity of
active drug required.
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Determination of occupied volume method
Example
• Prepare 10 suppositories, each containing 200 mg of a drug with a density of 3.0.
The base has a density of 0.9 & a prepared blank weighs 2.0 g.
Prepare required suppositories.

1. The average weight of mold is 2.0 gm


2. The quantity required for 10 suppositories is 2g X 10 = 20 g
3. The density ratio is 3.0/0.9 = 3.3
4. The amount of suppository base displaced by the active drug is 2.0 g / 3.3 = 0.6 g
5. The weight of the base required is 20 g – 0.6 g = 19.4 g
6. The quantity of active drug required is 0.2 x 10 = 2.0 g

• Answer: The required weight of the base is 19.4 g & the weight of the active drug
is 2g.

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Soluble Drug
• To prevent precipitation of drug powder
1. Melt the Base in order of melting point
2. Add Drug Powder after remove from water bath
3. Pouring into Mold and Let it solidify

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Insoluble Drug
1. Melt the Base in Casserole
2. Grind & Mixed with Viscous Melted base on
slab
3. Warm again on Water bath
4. Pour into Mold
5. Cooling wait for Solidify

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Lubricant / Lubricating Agent
1. Fatty Base / Hydrophilic
2. Water soluble Base
Liquid paraffin

Rx
• Soft soap 10 ml
• Glycerol 10 ml
• 95%EtOH 50 ml

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Method of preparation

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Melt the Base in Casserole

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Remove excess part via warmed
Spatula

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How to Remove Suppository

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Packaging & Storage
• Suppositories often are packaged in partitioned
boxes, that hold the suppositories upright. Glycerin
& Glycerinated gelatin suppositories are packaged
in tightly closed screw capped glass containers .
• Commercial suppositories are wrapped individually
in aluminum foil or PVC-polyethylene strip
packaging is the common place.
• Alternatively suppositories may be molded
directly into their primary packaging (molds
formed of plastic or foil).
• Suppositories with low-melting ingredients are
stored in a cool place. Theobroma oil suppositories
in particular , should be refrigerated.

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Evaluation of Suppositories
• Physical analysis
– Visual examination
• Color and the surface characteristics
• Odor
• Weight

• Melting range test


• Liquefaction or softening time test
• Suppository penetration test
• Mechanical strength/crushing test
• Dissolution test
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Melting range test
• This test is also called the macro melting
range test and is a measure of the time it
takes for the entire suppository to melt
when immersed in a constant-temperature
(37oC) water bath.
• The use of a U-shaped capillary tube to
determine melting point provides precise
information for excipient control and
consistency in production for those
suppositories containing soluble active
principles.
• The melting point can also be determined by
placing a small-diameter wire into the mold
containing the suppository melt before the
form solidifies.

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Liquefaction or softening time test

It consists of a U-tube partially submersed in


a constant temperature water bath. A
constriction on one side holds the
suppository in place in tube. A glass rod is
placed on top of the suppository, and the
time for the rod to pass through to the
constriction is recorded as the “softening
time”.

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Suppository penetration test
• A suppository penetration test can be used to
determine the temperature at which the
suppository becomes sufficiently soft for a
penetrating rod to drop through its length.
• The apparatus used is shown in Figure 9.6.
• The temperature is adjusted to that required for
the test, generally about 37◦C.
• The suppository is placed in the device and the
penetration rod gently moved into place. The
device holding the suppository and penetration
rod is lowered into the constant temperature bath
and a stopwatch is started.
• When the penetration rod drops through the
softened suppository the time is recorded.

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Mechanical strength/crushing test
• Suppositories can be classified as brittle or
elastic by evaluating the mechanical force
required to break them.
• Tests are used that measure the mass (in
kilograms) that a suppository can bear without
breaking.
• A good result is at least 1.8– 2 kg pressure. In
the example laboratory set-up shown in Figure
9.7, the suppository is positioned in an upright
position and increasing weights are placed on it
until it loses its structure and collapses.
• The purpose of the test is to verify that the
suppository can be transported under normal
conditions, and administered to the patient.

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Dissolution test
• Early testing was carried out by
simple placement in a beaker
containing a medium.
• In an effort to control the variation
in mass/ medium interface, various
means have been employed,
including a wire mesh basket, or a
membrane, to separate the sample
chamber from the reservoir.
• Samples sealed in dialysis tubing or
natural membranes have also been
studied.
• Flow cell apparatus have been used,
holding the sample in place with
cotton, wire screening, and most
recently with glass beads.

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