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Suppositories Outline
Introduction to suppositories
Physiology
Rectum, Vagina & Urethra
Applications
Advantages / disadvantages of suppositories
Suppository bases
Base classification
Cocoa-butter (Theobroma oil)
Hydrophilic suppository bases
Compressed tablet suppositories
Industrial manufacture
Compounding
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Introduction to Suppositories
Medicated solid dosage form generally intended:
Rectum
Vagina
Urethra
Usually vehicles melt or soften at body temp
1 % of all medications dispensed
Much more popular in Europe
Especially France
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Rectum
Terminal 15-19 cm of large intestine (LI)
Rectal Fluids
1. 2 - 3 mL
pH 6.8
Mild (lunak) environment / drug can change pH
LI function absorb H2O and electrolytes
Rectum usually empty of feces
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Rectal Blood Circulation
Main blood supply superior rectal artery
Blood return 3 blood veins
Superior hemorrhoidal vein
Middle hemorrhoidal vein
Inferior hemorrhoidal vein
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Rectal Blood Circulation
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Suppositories
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Urethra
Tube
Males 20 cm
females 4 cm
Poorly perfused by blood
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Targeted Delivery
Concentrate drug at site of action
Reduce side effects
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Advantages of Suppositories
Avoidance of oral and parenteral routes
Avoid first pass metabolism
Protect drug from harsh (merusak) conditions in stomach
Drug causes nausea and vomiting
Oral intake restricted before surgery
Patient suffering (menderita) from sever 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 compliance
Erratic and undesired absorption
Placement too high -> first pass metabolism
Installation may trigger defecation reaction
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
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Suppositories
Rectal
4 gm adult
1 gm child
Urethral
male 4 gm 100 – 150 mm
Female 60 – 75 mm
5 mm diameter
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Suppositories
Vaginal
3 – 5 gm
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Examples
Progesterone vaginal suppositories
Poor absorption and high 1st pass metabolism
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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Examples Cont.
Acetaminophen Methocarbamol & Aspirin
Aminophylline Miconazole
Aspirin Morphine Sulfate
Belladonna and Opium Nonoxynol 9
Bisacodyl Oxymorphone
Chloral Hydrate Pentobarbital
Chlorpromazine Prochlorperazine
Clindamycin Promethazine
Dinoprostone Propoxyphene and Aspirin
Ergotamine Tartrate & Senna
Caffeine Sulfanilamide
Glycerin Terconazole
Hydrocortisone Thiethylperazine
Hydromorphone Trimethobenzamide
Indomethacin Nystatin Vaginal
Mesalamine
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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 (Won't cover)
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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Drug Release Cont.
Drug release rate
If K drug won’t partition out of base
Water (i.e. rectal fluids)
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Cocoa-butter (Theobroma oil)
Most widely used base for Rx
Innocuous (tidak membahayakan)
Bland (menyenangkan)
Nonreactive
Melts at body temperature
Disadvantages
Fatty acids can become rancid (tengik)
Melt in warm weather
Liquefy (mencair) 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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Manufacture Method
Mfg. conditions produces a particular polymorph
Must control melt to get right polymorph!
Temperature
Rate of cooling
Rapid cooling locks in metastable form
Agitation
E.g.
Heat to T > 36 oC & rapid chill below 0 oC
Suppository melts or softens at room temp.
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Polymorphic Properties
α Melting point 24 oC
Rapid Rapid cooling of liquid to 0 oC
γ Melting point 18 oC
Rapid Rapid cooling of 20 oC liquid
e.g., pouring into cold mold
ß’ Melting point 28 to 31 oC
Crystallizes from Stirred Stirred liquid at 18-23 oC
ß' -> ß: 1-4 days depending upon conditions
ß Melting point 34 to 35 oC
Stable form
All forms convert to ß couple in days to a week
Won't work if need to fill Rx
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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 & Fattibase
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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 g
Glycerin 70 g
Gelatin 20 g
Vaginal suppositories (Above Rx used for)
Local application of antimicrobials
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Glycerinated Gelatin Cont.
Not as good for rectal delivery
Absorb H2O from mucosal membranes
Wet before use to:
Avoid/reduce “stinging”
Faster dissolution
Patient counseling leave in package
Will support mold and bacterial growth
Can use preservative
Propylparaben 0.02% & Methylparaben 0.18%
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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
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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Rx Note
Systemic Absorption
Suppositories prone to erratic absorption
i.e., formulation is critical
Use commercial products where available!
Local Action
Not as critical
Most bases hold drug in contact with target tissue
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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
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Base Selection Cont.
Cocoa butter has no emulsifier
Low water uptake
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
Non-tablet
Hand rolling and shaping
Fusion -> Molding from a melt
Compression molding
Not commonly done
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Hand Rolling & Shaping
Advantages
No equipment
No special calculations
No heat
Disadvantages
Difficult to manufacture
They’re not pretty
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Hand molding
Simplest & oldest method
Only use cocoa butter (theobroma oil)
Procedure
Grate base
Active ingredients finely powdered or dissolved in alcohol,
mixed with wool fat to help incorporation with base
Kneaded active ingredients into base with mortar and
pestle
Roll Mass into cylindrical rod on pill tile
Cut rod to desired length; adjusted by slicing
Wrap individually in 3 x 3 inch foil squares
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Fusion
Advantages
Elegant appearance
Don’t need good hands
Disadvantages
Heat
Equipment: need molds, etc.
Special Calculations
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Molding From a Melt
Steps
– Melt base
Incorporating other ingredients and drug
Pouring the melt into mold
Allowing the melt to congeal
Remove from mold
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Molds
Stainless steel
Aluminum
Brass
Plastic
High speed molding machine
3500-10000/hour
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Mold Calibration
Determine the volume of each cell in mold
Pour in base & solidify
Weigh base from each cell
Put in beaker & melt to get volume
Calculate weight and volume of each cell
Different bases will have different ρ's
e.g. (assume 2 mL cavity)
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Density Factors
Dose Calculation
1) Calibrate mold
2) Calculate amt Drug
3) Calculate total suppository weight
drug + base
4) Calculate base needed by difference
Use “Density Factors” to calculate amt. of
base displaced by drug
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Density Factors – Cocoa Butter
1 g of cocoa butter = x g of drug
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e.g. Calculation
Rx
Aspirin 100 mg
Cocoa Butter q.s.
M & ft. Suppositories #6
Sig: I supp pr q4-6 hours prn pain and fever
Calculations (make for 2 extra)
Mold calibration 2 g/cavity
Aspirin ⇒ 8 X 100 mg = 800 mg
8 X 2 g = 16 g
0.8 g Aspirin X (1 g CB/1.3 Aspirin) = 0.615
Base ⇒ 16 g – 0.615 g = 15.38 g
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Clotrimazole and Clindamycin Suppositories
MANUFACTURING DIRECTIONS
Dissolve items 1 and 2 in item 5.
Heat item 4 in item 6 in a separate vessel and add item 3.
Mix well and add to step 1.
Fill suppository 2.0 g each.
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Clotrimazole and Clindamycin Suppositories
MANUFACTURING DIRECTIONS
Add and mix all ingredients.
Heat to 70°C and mix well.
Cool to 40°C and fill.
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Diclofenac Sodium Suppositories
MANUFACTURING DIRECTIONS
Load items 2–4 in the fat-melting vessel and heat to 55°C.
Transfer to a mixing vessel through filter sieves; set the temperature to
50°C.
Add items 1 and 5 to step 2. Mix at 10 rpm and homogenize at speed I
for 15 minutes at 0.6 bar vacuum.
Cool down to 50°–55°C.
Transfer into storage vessel and set temperature at 50°C.
Fill 1800 mg in a suppository mold.
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Miconazole Nitrate Vaginal Suppositories 400 mg
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MANUFACTURING DIRECTION
1. Load items 2 and 3 in the fat-melting vessel and heat to 50° ± 3°C.
2. Check the molten mass for phase separation.
3. Transfer the molten mass to the mixer through filter sieves. Set the
temperature at 40° ± 2°C.
4. Load item 1 to the mixer containing molten witepsol (items 2 and 3).
5. Carefully mix the powder with the witepsol melt.
6. Set the mixer at temperature 40° ± 2°C, speed 10 rpm (manual mode),
and mix for 10 minutes.
7. Set the mixer at temperature 40° ± 2°C, mix under vacuum 0.6 bar.
8. Homogenize at low speed while mixing for 5 minutes.
9. Homogenize at high speed while mixing for 3 minutes.
10. Continue mixing of the mass under vacuum in mixer.
11. Heat the storage vessel, set the temperature at 40° ± 2°C.
12. Transfer the molten mass from the mixer to the storage vessel.
13. Hold the mass at 40° ± 2°C while mixing continuously at low speed. Fill.
14. Fill 2,700 mg.
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Suppository Equipment
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Glycerin Suppository Manufacturing System
machine could mold 2,400,000 per day
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