Pharmaceutics 356C

Chapter 12

Suppositories

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 Suppositories

• Definition: Solid dosage form

intended for insertion into the body
orifices where it melts, softens, or
dissolves—and exerts localized or
systemic effects
• Types: Rectal, vaginal
Also—Urethral, aural, nasal
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 Suppository
Characteristics
• Shape & Size
--to promote insertion and facilitate
retention
• Must release medicaments
--Body temp 37oC– so what about
melt?
--Suppository must absorb moisture
from surrounding area to dissolve drug
from the base—Disintegration!
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 Suppository Sizes

• Rectal (99%):
--32 mm length, cylindrical, tapered ends
--Weighs about 2 gm (USP--base of Cocoa butter
--Note: For infants & children—1gm (1/2 size of
adult)
• Vaginal (Pessaries) (1.0%):
--Shape—Globular, oviform, or conical
--Weight about 2 - 5 gm (base)
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 Suppository Sizes
• Urethral (Bougies):
--Slender, pencil shaped
--Male: 3-6 mm diameter, 140 mm length, 4 g
--Female: 1.5-3.0 mm diam., 70 mm length, 2 g
• Nasal or Aural (Nose or Ear Cones):
--Rarely used—pencil-shaped, 32 mm in length
--Weight about 5 gm (cocoa butter)
Nasal supp.: made w/ glycinerated gelatin
base
Aural supp.: made with cocoa butter
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 Suppository Packaging
• In general—Best to keep all supp refrigerated
--Base of Cocoa Butter: Store < 30oC
--Base of glycerinated gelatin: Store <35oC
--Base of PEG: High m.p. so usually OK slightly warm

• Containers—Tightly closed glass (i.e. glycerin is very

hygroscopic)
--Individually wrapped foil (Unwrap & insert)

• Environment—Important due to base

--High humidity—absorbs water from atmosphere
--Low humidity—loose water to atmosphere--brittle
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Examples:

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 Dissolution of
•
Suppositories
In vitro/in vivo correlation:
--established for each suppository product
• Effect of solubility:
-- Lipophilic drug
- slow release in oily base
- moderate release in water soluble/miscible
base (drug dissolves slowly in aqueous compartment)
-- Water soluble drug
- rapid release in oily base
- rapid to slow release in water soluble/miscible base
(depends on rate of dissolution of base and diffusion of drug
out)

• Effect of Viscosity:
--If viscous mass, drug released slowly
• Effect of drug particle size:
--decrease P.S.--? (conc-time curve)
--especially watch out for brand substitutions

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 Uses of Suppositories

• Local Action:
-- Drug is intended to remain in area where it
will have effect (relieve constipation,
hemorrhoidal pain)
• Hemorrhoidal Suppository—for: vascularized,
finger-like protrusions from anus caused by
stress, tension, travel, constipation, standing
(Attention Pharmacists!!)

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 Uses of Suppositories
• Ingredients in hemorrhoidal formulations:
--Local anesthetics—Benzocaine, lidocaine, pramoxine HCl (pain)
--Vasoconstrictors—Epinephrine HCl, Ephedrine sulfate,
phenylephrine HCl (Itching)
--Astringents—Calamine, Zinc Oxide (Itching, tightening mucosa)
--Soothing & protecting agent—lanolin - act as a physical barrier—not
absorbed
• Laxative Suppositories:
--Glycerin Supp.—Causes laxative action (humectant?)
--Contents—PEGs—Increase MW, Increase mp
Bisacodyl (Ducolax®)
Senna Concentrate (Senakot®)
• Suppositories have Stability Problems!
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 Uses of Suppositories

• Systemic Action:
--Mucous membranes of rectum and vagina permit
absorption of soluble drugs
--Rectum well vascularized (hemorrhoidal vein)
• Advantages:
--Rapid absorption
--pH—Usually about 40% of drug is absorbed
--First Pass Effect - NO
--Good for patients (Adult, Pedi) who cannot swallow
medication or who are vomiting

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 Common Drugs for Systemic
Absorption in Suppositories
• Doses are relatively large
• Common Drugs:
--Aminophylline—Asthma
--Indomethacin—NSAID
--Prochlorperazine—Nausea, tranquilizer
--Ondansetron—Nausea & Vomiting
--Chloral Hydrate—Hypnotic
--Oxymorphone HCl—Narcotic analgesic
--Aspirin—Analgesic, antipyretic
--Acetaminophen—Analgesic
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 Suppository Bases
• Properties:
--Non-irritating
--Chemically and physiologically inert
--Firm enough to be inserted (m.p. impt)
--Can control the release of drug with base
i.e. Glycerinated gelatin and PEG

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Oil Soluble Suppository Bases
• Oil Soluble Bases (Fatty, Oleaginous):
--Most frequently used
• Examples:
--Cocoa Butter, NF (Theobroma Oil)
-Fat from roasted seeds of Theobroma Cocoa
-Softens (molten at 30oC, melts at about 35oC, melted at 37oC)
-Mixture of triglycerides
-Light yellow color, pleasant odor
-Exhibits polymorphism (due to the triglyceride content)
-Metastable (Alpha form)—when carelessly melted
(solidifies?)
-Stable (Beta form)—greater stability
--Palm Kernel Oil
--Cottonseed Oil

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Physical State of Bases

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 Oil Soluble Suppository Bases
• Problems with Theobroma Oil:
--Some drugs lower mp (volatile oils,
phenolic drugs, chloral hydrate)—Eutectics
--Use solidifying agents
--Cetyl Esters Wax NF 20%--mp = 45oC
--White Wax NF 4-6%--mp = 62oC
• Note: If use < 3% of these—Also form a eutectic
• Thus:
--Amount of drug
--Type of drug
Both determine amount of wax that is needed
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 Oil Soluble Bases
• Witepsols
– Mixtures of synthetic triglycerides of various molecular weights
– Similar to cocoa butter, but no polymorphism
– Contain emulsifiers – will absorb limited amounts of water
– Releases well from molds
• Fattibase
– MP – 32.0C to 36.5C
– Opaque, white base of palm, palm kernal and coconut oils,
glyceryl monostearate and polyoxylstearate
– Good stability, releases well from molds
– Faster drug release than cocoa butter because it is emulsifiable

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 Water Soluble Suppository
Bases
• Glycerinated Gelatin Base:
--Requires lubricated mold
--Vaginal Suppositories
--Not for Rectal Use
--Swelling of gelatin in rectum
--Glycerin is hygroscopic—attracts
moisture, therefore is dehydrating
--dissolves in mucus secretions but takes
long time
--Can hold half its volume of aqueous solution
--Base is translucent, resilient, hygroscopic so
store in airtight containers
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Glycerinated Gelatin - continued
• Formulation:
--Drug + Water = 10 g
--Glycerin = 70 g
--Gelatin = 20 g

Dissolve/suspend drug in water; mix with

glycerin; add to gelatin slowly
(clumping); apply low heat to melt
gelatin stirring gently (no air)
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 Water Soluble Suppository
Bases
• PEG Base:
--Polyethylene glycol is a polymer of ethylene oxide & water
--MWs:
--PEG 200-400—Liquid at RT, clear, colorless
--PEG 1000-1500—Semisolid, wax-like, white
--PEG 1540-20K—Solid, wax-like, white (3350 & 8000)
• Note: PEG 20K is more viscous and shows slower drug
dissolution than PEG 3350
• Properties:
--Does not melt at body temp, but slowly dissolves in body fluids
--Due to high mp, not necessary to refrigerate unless in hot
environment
--PEG Supp need to contain at least 20% water—to prevent
irritation
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--if not, instruct patient to dip in water prior to use
 Water Soluble Suppository Bases
• Polybase
– Mixture of PEGs and polysorbate 80
– Water miscible, dissolves, does not melt
– MP 60C to 71C
– Good stability at RT

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 Drugs into Suppositories
• Drugs insoluble in Theobroma Oil
--Zinc Oxide, Bismuth Subgalate, Iodoform, ASA—Spatulate powder with
molten base
• Insoluble Liquid substances
--Can form W/O Emulsion with cocoa butter—can absorb 10-20% of
liquids
• Volatile liquids soluble in suppository base
--Will lower mp—Eutectic
--Use another wax to increase mp—i.e. White wax
• Solid Substances Soluble in Suppository Base
--Phenol, Resorcinol (Anti-itching), Chloral Hydrate
--If soluble in water, dissolve in small amount of water--if soluble in
glycerin, dissolve in small amount of glycerin—Incorporate into Supp
base
--If large amount of drug is present—can add wax to increase mp—or 22
change base
 Other Excipients That May Be Required:
• Consider the following used in suppositories:
– Water
• Avoid if possible
• Enhances oxidation of fatty bases
• Promotes microbial growth (need preservative)
• Accelerates reactions between base, drug, excipients
– Preservatives and antioxidants
• Most compounded do not contain
• Include if:
– Water is used
– Oxidizing base
– Drug is stable for proposed shelf-life
– Suspending agents (1-10% Silica Gel)
• Use if viscosity of molten base is low 23
Other Excipients - Continued
– Toughening agents (1-2% Tween 80; glycerin; propylene glycol;
castor oil; sweet almond oil)
• For high MP bases (synthetic stearates, highly hydrogenated fats,
high level of other ingredient >30%) – may become brittle, fracture
– Avoid freezing
– Confirm MP not lowered too much
– Agents to assist in release from mold (Mineral oil for water
soluble base and glycerin/PG for fatty base)
• Use if sticking occurs; most modern bases release well
– Agents that modify drug-release rate (Delay - methyl cellulose;
alginic acid; Speed-up – emulsifying agents)
• Release depends on:
– Melting time
– Dissolution time
– Diffusion rate of drug from base
– Dissolution rate of drug in body fluids
– Agents that alter the melting point
• Lower the MP (Sweet almond oil; liquid paraffin)
• Raise the MP (White wax, cetyl esters wax; beeswax) 24
 Methods of Preparation of
Suppositories
• Molding
--Melt Base (molten) + Drug(s)—determine
amount of base for each
--Pour melt into molds—lubricate mold with small
amount of mineral oil or glycerin
--Allow melt to cool and congeal
--Remove from mold
• Compression
--Uses special supp machine to compress paste-
like mass into suppository (Like tablets—
Monistat® 3)
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Examples of Molds

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 When Preparing – Consider:
• If no formula, try one for a drug with similar
structure
• Always allow for about 5% waste
• Use vehicle that is nontoxic and nonirritating
• Base must be compatible with drug and stable
on storage
• Use inexpensive, disposable molds which
obviates the need for cleaning and removal;
Molds serve as packaging to the patient
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 Preparation Example with Molds

Ingredients are melted and poured into mold.

Suppository mold was separated after cooling down

Suppositories are removed from the mold

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 When Preparing – Consider:
• Base should NOT interfere with
bioavailability
• If drug dissolves in base, this will most
likely decrease MP
• If drug is relatively dense, use a base that
crystallizes rapidly
• Minimize use of surfactants – adsorb
many drugs
• Volatile substances decrease MP
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 Expiration Dating:
• In absence of other data, use USP
guideline for drugs repackaged from
multidose containers into unit dose
packages:
– Never assign expiration date that:
• Exceeds 6 months
• Is 25% of the remaining time between the date of
compounding and the shortest expiration date of
the ingredients
• Use the shortest of above

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 Indications of Instability in
Suppository Formulations
• Excessive softening
• Drying or shriveling
• Staining of the packaging material
• Hardening
• Discoloration

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 To Maximize Bioavailability,
Consider:
• Use smallest particle size
• Use ionized rather than unionized to enhance
water solubility
• Consider effect of pH on partitioning and
absorption
• Emulsification will increase contact area
between fatty bases and aqueous rectal
compartment
• Suppository may migrate to various levels of
lower GI tract – first pass metabolism
• Rheological properties of the base

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 To Maximize Bioavailability,
Consider:
• Absorption rates from theobroma oil are
enhanced by adding:
– Polyoxyethylene sorbitan monostearate, SLS
• Solubility in base:
– Testosterone dissolves in hot Witepsol H but
crystallizes out during cooling (High Bio)
– Testosterone forms solid solution with theobroma oil
(Poor Bio)
• W/O emulsion of water-soluble drugs yields poor
bioavailability
– Drug must partition from W into O, and then into W
again (aqueous rectal/vaginal compartment)

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 To Maximize Bioavailability,
Consider:
• Absorption from theobroma oil enhanced
by addition of:
– Polyoxyethylene sorbitan monostearate
(Polysorbate 60)
– SLS
– Cetyltrimethylammonium bromide
– All increase spreading and degree of contact
of base with mucosa

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 Quality Assurance:
• Rate of melting or disintegration –
– BP disintegration test for suppositories
• Rate of dissolution –
– Dissolution apparatus
• Content uniformity –
– Important when < 2 mg / suppository OR <
2% w/w of API
• Texture uniformity –
– Section longitudinally and laterally; ensure
each section is smooth, uniform surface
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 Quality Assurance:
• Weight uniformity –
– Weigh 20 suppositories; NMT 2 deviate by >
5% from average weight; and not more than
10%
• Packaging container integrity –
– Measure weight gain or loss of suppositories
after storage

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 Commercially Available
Suppository Products

• Glycerin Suppository, USP (Various Manuf)

--Glycerin 91 g
--Sodium Stearate 9g
--Water 5g
--Heat Glycerin to 120oC
--Dissolve Sodium Stearate in Glycerin
--Add water
--Pour into molds
--Rectal Evacuant—Glycerin & Sodium Stearate have
irritating properties to initiate defecation process
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 Commercially Available
Suppository Products

• Indomethacin Suppositories, USP

(Merck)
--Base is PEG 3350 and PEG 8000
--NSAID (causes gastric upset)
• Promethazine HCl Suppositories, USP
(Phenergan, Wyeth-Ayerst)
--Base is cocoa butter and white wax--Why?
--Anti-emetic, antihistamine and sedative 38