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Pharmaceutics IIPharmaceutics II

SuppositoriesSuppositories

Suppositories: OutlineSuppositories: OutlineSuppositories: OutlineSuppositories: Outline

� Introduction – definitions

� Rectal route

� General applications of suppositories

� Advantages

� Disadvantages

� Factors Affecting Rectal Absorption

� Suppository bases

� Fatty or oleaginous bases

� water-soluble or water-miscible bases

� miscellaneous bases

� Preparation methods of suppositories

� Vaginal suppositories and inserts

� Quality control, packaging, storage, and use

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Suppositories: DefinitionSuppositories: DefinitionSuppositories: DefinitionSuppositories: Definition

� Suppositories (from the Latin supponere,

meaning "to place under") are solid dosage forms

intended for insertion into body orifices, in the

rectum and vagina and occasionally urethra,

where they melt (fatty bases) or dissolve (water

soluble bases) and exert local or systemic effects.

Supp

type

Rectal Vaginal

(pessaries)

Urethral

(bougies)

Size 26 - 32 mm 25 mm Male:140 mm

Female: 70mm

Shape Cylindrical

(bullet) with

tapered end

globular,

oviform, or

cone-shaped

slender, pencil-

shaped

weight Adults: 2 g

Infants: 1g

5 g Male: 4 g

Female: 2g

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General applications of rectal suppositoriesGeneral applications of rectal suppositoriesGeneral applications of rectal suppositoriesGeneral applications of rectal suppositories

� The medicament may be administered in the form of asuppository for:

I. A local effect. For example, local anaesthetics (dibucaine andcyclomethycaine), corticosteroids (hydrocortisone) andastringent (zinc oxide) drugs are administered in suppositoriesfor the treatment of pain, itching, irritation and inflammationassociated with haemorrhoids, e.g.

II. To promote evacuation of the bowel (laxatives andcathartics). This may be achieved by a physical orpharmacological effect: glycerin and bisacodyl.

III. A systemic effect for drugs that are absorbed through themucus membranes of the rectal cavity: ondansetron (nauseaand vomiting), prochlorperazine and chlorpromazine (nauseaand vomiting and as a tranquilizer), oxymorphone (opioidanalgesia), ergotamine tartrate (migraine syndrome),indomethacin (a NSAID and antipyretic), paracetamol

(analgesic and antipyretic).

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Advantages Of The Rectal RouteAdvantages Of The Rectal RouteAdvantages Of The Rectal RouteAdvantages Of The Rectal Route

� Advantages of the rectal route for systemic effectsover oral therapy:

(1) Avoids drugs decomposition or inactivated by the pH orenzymatic activity of the stomach or intestines.

(2) Avoids irritation of the stomach caused by some drugs.

(3) Avoids destruction in the liver (first-pass effect).

(4) The route is convenient for administration of drugs topatients who are unable or unwilling to swallowmedication.

(5) An effective route in the treatment of patients withvomiting.

(6) is not influenced by food, gastric emptying etc.

� The rectal route may also be an alternative to parenteraladministration; a very rapid systemic effect occurs whenthe drug is given as a soluble solution (enema).

Disadvantages of Rectal AdministrationDisadvantages of Rectal AdministrationDisadvantages of Rectal AdministrationDisadvantages of Rectal Administration

1. Patient acceptability.

2. Small absorption area.

3. The fluid content of the rectum is less smaller than thatof the small intestine, and this may cause pain andproduce problems with the dissolution of some drugs.

4. Some drugs are degraded by the micro-organisms ofthe rectum.

5. Some drugs irritate the mucus membrane.

6. Defecation may interrupt absorption.

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Factors Affecting Rectal AbsorptionFactors Affecting Rectal AbsorptionFactors Affecting Rectal AbsorptionFactors Affecting Rectal Absorption

I. Physiologic factors

II. Physicochemical factors of the drug

III. Physicochemical factors of the base

Physiologic FactorsPhysiologic FactorsPhysiologic FactorsPhysiologic Factors

� The rectum is a hollow organ or tube approximately15-20 cm long.

� The rectal wall is formed by an epithelium one cell layer.

� In the resting state, the rectum is not motile.

� The absence of villi indicate that the rectum is not anatural absorption organ.

� The surface area is small (200 - 400 cm2) comparedwith that of the small intestine containing villi (200m2)i.e. a 10-thousand fold difference.

� However, there is abundant vascularization of thesubmucosal region of the rectum wall with blood andlymphatic vessels.

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Physiologic FactorsPhysiologic FactorsPhysiologic FactorsPhysiologic Factors

� Among the physiologic factors that affect drug

absorption from the rectum are:

1. Colonic contents.

2. Circulation route.

3. pH and lack of buffering capacity of the rectal

fluids.

Physiologic FactorsPhysiologic Factors: : Colonic ContentColonic ContentPhysiologic FactorsPhysiologic Factors: : Colonic ContentColonic Content

� The rectum gives greater absorption when it is

empty from fecal matter because the drug has a

greater opportunity to make contact with the

absorbing surface of the rectum and colon.

� An evacuant enema may be administered to

empty colon before the administration of a

suppository.

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Physiologic FactorsPhysiologic Factors: : Circulation RouteCirculation RoutePhysiologic FactorsPhysiologic Factors: : Circulation RouteCirculation Route

� The lower hemorrhoidal veins

surrounding the rectum receive the

absorbed drug and initiate its

circulation throughout the body,

bypassing the liver, thereby

avoiding drug destruction in the

liver.

� Drugs that are absorbed by the

superior hemorrhiodal veins are

subject to first-pass metabolism in

the liver.

� Lymphatic circulation also assists in

the absorption of rectally

administered drugs.

middle

superior

lower

skin

Hemorrhoidal veins

Physiologic FactorsPhysiologic Factors: : pHpHPhysiologic FactorsPhysiologic Factors: : pHpH

� pH of the rectal fluids is essentially neutral (pH 7

– 8) with no effective buffer capacity. In these

conditions most drugs are chemically stable.

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Physicochemical Factors of the DrugPhysicochemical Factors of the DrugPhysicochemical Factors of the DrugPhysicochemical Factors of the Drug

Drug solubility and suppository formulation

Solubility in

Choice of baseFat Water

Low High Fatty base

High Low Aqueous base

Low Low Indeterminate; micronized drug particles is used

1.The relative solubility of the drug in lipid and in water.

A lipophilic drug that is distributed in a fatty suppository base in low

concentration has less tendency to escape to the surrounding

aqueous fluids than a hydrophilic substance in a fatty base. Water

soluble bases (e.g polyethylene glycols) that dissolve in the anorectal

fluids release for absorption both water-soluble and oil-soluble drugs,

but some of these bases may interact with hydrophilic drugs thus

retarding their absorption.

Physicochemical Factors of the DrugPhysicochemical Factors of the DrugPhysicochemical Factors of the DrugPhysicochemical Factors of the Drug

2. The particle size of a dispersed drug.

For undissolved drugs in a suppository, the size of the

drug particle will influence its rate of dissolution and its

availability for absorption. The smaller the particle, the

more readily the dissolution of the particle and the

greater the chance for rapid absorption.

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Physicochemical Factors of thePhysicochemical Factors of the

Suppository BaseSuppository Base

Physicochemical Factors of thePhysicochemical Factors of the

Suppository BaseSuppository Base

1. Ability to melt, or dissolve at body temperature

2. Ability to release the drug substance

3. Base’s hydrophilic or hydrophobic character

� The more drug a base contains, the more drug

will be available for absorption.

Nature of the BaseNature of the BaseNature of the BaseNature of the Base

� If the base interacts with the drug to inhibit its release,drug absorption will be impaired or even prevented.

� For example, the bioavailability of aspirin suppositories isonly 40% with retention time of 2 hours. Therefore, theabsence of any interaction between the medicinal agentand the suppository base should be ascertained beforeor during formulation.

� If the base irritates the mucous membranes of therectum, it may initiate a colonic response and prompt abowel movement, preventing complete drug release andabsorption.

� Long-acting or slow-release suppositories are alsoprepared. Morphine sulfate is prepared by using alginicacid as a base (a polymer that swells and forms a gel inthe biological fluids), which will prolong the release of thedrug over several hours (5-7).

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Properties of an Ideal BaseProperties of an Ideal BaseProperties of an Ideal BaseProperties of an Ideal Base

� An ideal base should:

1. Melt (fatty base) or disintegrate, i.e. mix and dissolve, inthe rectal fluids (water soluble base) at bodytemperature (temperatures just below bodytemperature)

2. Release drug easily from the suppository

3. Be of the correct viscosity when molten to inhibit drugsedimentation but still allow the melt to flow into themould and over the mucus membranes

4. Be non-toxic and non-irritant to sensitive and inflamedtissue

5. Show chemical and physical stability

6. Be compatible with a range of drugs

Classification of suppository baseClassification of suppository baseClassification of suppository baseClassification of suppository base

fatty or oleaginous

baseswater-soluble or

water-miscible bases

miscellaneous bases:

lipophilic and hydrophilic

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Fatty or Oleaginous BasesFatty or Oleaginous BasesFatty or Oleaginous BasesFatty or Oleaginous Bases

� The most frequently used suppository bases,especially:

1) cocoa butter.

2) hydrogenated fatty acids of vegetable oils, such aspalm kernel oil and cottonseed oil.

3) compounds consisting of glycerides of higher-molecular-weight fatty acids, such as glycerylmonostearate and glyceryl monopalmitate.

� The bases in many commercial products employcombinations of these types of materials to achievethe desired hardness under conditions of shipmentand storage and the desired quality of submitting tothe temperature of the body to release theirmedicaments

Specifications for Fatty BasesSpecifications for Fatty BasesSpecifications for Fatty BasesSpecifications for Fatty Bases

� Melting Range

Since fats do not have sharp melting points their meltingcharacteristics are expressed as a range indicating thetemperature at which the fat starts to melt and thetemperature at which it is completely melted. Thisrange should be narrow enough to give rapidsolidification during manufacture to prevent aggregationof suspended drug but slow enough to prevent faultsand fissures forming.

� Acid Value

The acid value is the number of milligrams of potassiumhydroxide required to neutralise the free fatty acids in1gm of base. Low acid values (below 3) are importantfor good suppository bases as free acids may react withother ingredients and can also cause irritation when incontact with the mucus membranes.

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Specifications for Fatty BasesSpecifications for Fatty BasesSpecifications for Fatty BasesSpecifications for Fatty Bases

� Water Number (Hydroxyl Value)

� The water number is the weight of water (gm) that canbe incorporated into 100gm of base. This number isrelated to the amount of mono- and di-glyceridespresent in the base. High water numbers aid theincorporation of drugs, but are avoided with drugs thatundergo decomposition by hydrolysis.

� The water number can be increased by the addition ofsurface active agents and other emulsifiers. Thissometimes leads to the formation of a w/o emulsion inthe rectum which should be avoided because itencourages slow release.

Specifications for Fatty BasesSpecifications for Fatty BasesSpecifications for Fatty BasesSpecifications for Fatty Bases

� Iodine Number

The iodine number expresses the weight (gm) of iodine

that reacts with a 100 gm of suppository base. The

value gives an indication of the amount of unsaturated

material. High iodine values indicate that rancidity on

storage might occur. Values below 7 are usually

specified.

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Cocoa ButterCocoa ButterCocoa ButterCocoa Butter

� Cocoa Butter is the fat obtained from the roasted seedof Theobroma cacao. It is a mixture of triglycerides ofsaturated and unsaturated fatty acids of which oleic acidcontributes up to one third of the fatty acid components.

� It is a solid fat at room temperature, but melts between30 and 36°C, (just below body temperature).

� It has been used for many years because it is non-irritant and miscible with many medicaments. However,this base is no longer used because of its manydisadvantages.

Disadvantages of Disadvantages of Cocoa ButterCocoa ButterDisadvantages of Disadvantages of Cocoa ButterCocoa Butter

1. Marked polymorphism. It exhibits at least fourdifferent crystalline states, α, γ, β', and β crystals, withmelting points of 17, 23, 26, and 34–36°C respectively,of which the β−form is the stable polymorph. Themetastable polymorphs may gradually revert to thestable β−form on storage; this takes a few days.

2. Melting points are reduced by many solubleingredients, such as phenol and chloral hydrate. In thiscase, solidifying agents like cetyl esters wax (about20%) or beeswax (about 4%) may be added.

3. It does not shrink on cooling, thus a lubricant isrequired to enable removal from the suppository mould.

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Disadvantages of Disadvantages of Cocoa ButterCocoa ButterDisadvantages of Disadvantages of Cocoa ButterCocoa Butter

4. It exhibits rancidity on storage, due to oxidation of

the unsaturated glycerides.

5. Batch to batch variations. The physical properties of

batches of cocoa butter from different sources may

vary even though they are all within the appropriate

specifications.

6. Poor water absorbing ability.

Transition between cocoa butter polymorphs: Transition between cocoa butter polymorphs:

alpha and beta formsalpha and beta forms

Transition between cocoa butter polymorphs: Transition between cocoa butter polymorphs:

alpha and beta formsalpha and beta forms

beta crystals alpha crystals

slow transition (several days)

stable form

Solid at room T

(34-36°C)

metastable form

quickly melted and quickly chilled

Not solid at room T

(17°C)

avoided by

slow melting

Takes place

spontaneously

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SemiSemi--syntheticsynthetic Fatty BasesFatty BasesSemiSemi--syntheticsynthetic Fatty BasesFatty Bases

� Fattibase: triglycerides from palm, palm kernel,and coconut oils with self-emulsifying glycerylmono-stearate and polyoxyl stearate.

� Wecobee bases: triglycerides derived fromcoconut oil.

�Witepsol bases: triglycerides of saturated fattyacids C12–C18, their melting ranges vary from 32- 42oC .

Some properties of fatty suppository bases

Acid

content

Hydroxyl

number

Iodine

number

Cocoa butter <5 0 34-38

Semi-synthetic fatty bases <2 <5-30 <3

WaterWater--Soluble and WaterSoluble and Water--Miscible BasesMiscible BasesWaterWater--Soluble and WaterSoluble and Water--Miscible BasesMiscible Bases

� The main members of this group are

glycerinated gelatin and polyethylene glycols.

� The melting points of these bases are well over

body temperature, making them especially suited

for application in tropical climate.

� For dissolution the available volume of rectal fluid

(1-3 mL) is too small, and therefore these bases

attract water from the rectal cells, resulting in a

painful sensation for the patient. The

incorporation of at least 20% water and

moistening before insertion can help to reduce

this problem.

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Glycerinated gelatin suppositoriesGlycerinated gelatin suppositoriesGlycerinated gelatin suppositoriesGlycerinated gelatin suppositories

suppositories Rectal + Vaginal Urethral

gelatin 20% 60%

glycerin 70% 20%

water or a

solution or

suspension of

the medication

10% 20%

Advantages

over cocoa

butter

prolonged local action easier to insert (cocoa

butter is brittle and

soften rapidly)

disadvantages because of hygroscopicity of glycerin they

absorb moisture (must be protected), and

may cause dehydration and irritation of the

tissues upon insertion (water is added)

Polyethylene Glycol SuppositoriesPolyethylene Glycol SuppositoriesPolyethylene Glycol SuppositoriesPolyethylene Glycol Suppositories

Polyethylene glycols are polymers of ethylene

oxide and water prepared to various chain

lengths, molecular weights, and physical states.

where m represents the average number of oxyethylene

groups.

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Polyethylene Glycol SuppositoriesPolyethylene Glycol SuppositoriesPolyethylene Glycol SuppositoriesPolyethylene Glycol Suppositories

M w Melting ranges state

300 –15 to –18°C Liquid

400 4-8°C Liquid

600 20-25°C Liquid

1000 37-40°C Semi-solid

1450 43-46°C solid

3350 54-58°C solid

4600 57-61°C solid

6000 56-63°C solid

8000 60-63°C solid

The most commonly used polyethylene glycol:

Polyethylene Glycol SuppositoriesPolyethylene Glycol SuppositoriesPolyethylene Glycol SuppositoriesPolyethylene Glycol Suppositories

� Polyethylene glycol suppositories do not melt at bodytemperature but rather dissolve slowly in the body'sfluids.

� polyethylene glycol mixtures with melting pointsconsiderably higher than that of body temperature, givesthe following advantages over cocoa butter:

1. slow release of the medication from the base

2. convenient storage of without danger of their softening inwarm weather

3. Do not melt in the fingertips

4. Do not leak from the orifice after insertion

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Polyethylene Glycol SuppositoriesPolyethylene Glycol SuppositoriesPolyethylene Glycol SuppositoriesPolyethylene Glycol Suppositories

Formula A B

PEG 1000 96% 75%

PEG 4000 4% 25%

Formula A melts at a lower temperature and may need

refrigeration during the summer months but is useful where

rapid disintegration is required. Formula B is more heat

stable than A and is useful when a slow release of active

ingredients is preferred.

Various combinations of these polyethylene glycols may be

combined by fusion to achieve a suppository base of the

desired consistency and characteristics. For example:

Miscellaneous BasesMiscellaneous BasesMiscellaneous BasesMiscellaneous Bases

� The miscellaneous group of bases are mixtures ofoleaginous and water-soluble or water-misciblematerials. These materials may be chemical or physicalmixtures. Some are preformed emulsions, generally of thewater–oil type (result in slow drug release), or they may becapable of dispersing in aqueous fluids.

� One of these substances is polyoxyl 40 stearate, asurface-active agent that is employed in a number ofcommercial suppository bases. Polyoxyl 40 stearate is amixture of the monostearate and distearate esters ofmixed polyoxyethylene, the average polymer length beingequivalent to about 40 oxyethylene units. The substance isa white to light tan waxy solid that is water soluble. Itsmelting point is generally 39° to 45°C.

� Mixtures of many fatty bases (including cocoa butter) withemulsifying agents capable of forming water–oil emulsionshave been prepared. These bases hold water or aqueoussolutions and are said to be hydrophilic.

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hand rolling

and shaping

Molding

Compression

Preparation

methods

of

Suppositories

The most

frequently

employed both

on a small scale

and on an

industrial scale

It is historic

and not used

any more

Suppository MoldsSuppository MoldsSuppository MoldsSuppository Molds

� Molds in common use today are made from stainlesssteel, aluminum, brass, or plastic.

� The molds, which separate into sections, generallylongitudinally, are opened for cleaning before and afterpreparation of a batch of suppositories, closed when themelt is poured, and opened again to remove the coldmolded suppositories.

� Care must be exercised in cleaning the molds, as anyscratches on the molding surfaces will take away from thedesired smoothness of the suppositories.

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Suppository moldsSuppository moldsSuppository moldsSuppository molds

Small-scale

(pharmacy)Large-scale

(industry)

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Preparation by MoldingPreparation by MoldingPreparation by MoldingPreparation by Molding

� Molding steps include:

(a) melting the base

(b) incorporating any required medicaments

(c) pouring the melt into molds

(d) allowing the melt to cool and congeal into suppositories

(e) removing the formed suppositories from the mold

� Cocoa butter, glycerinated gelatin, polyethylene glycol, and mostother bases are suitable for preparation by molding.

Mold lubrication� The chosen lubricant must be immiscible with the base andcompatible with the medicament and any other formulationadditives. For theobroma oil (fatty bases), an alcoholic solution ofsoft soap and glycerol is the traditional lubricant. Liquid paraffinis a suitable lubricant for the water-miscible bases.

Calibration of the MoldCalibration of the MoldCalibration of the MoldCalibration of the Mold

Mold with

specific volume

Same volumes but

different weights

because of the

difference in

densities of materials

Density =Mass

volume

Each mold should be

calibrated for the used base

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Calibration of the MoldCalibration of the MoldCalibration of the MoldCalibration of the Mold

� To determine the weight of the suppositories:

1. Molded suppositories from base material alone areprepared.

2. suppositories are removed from the mold and weighedand the total weight and average weight of eachsuppository are recorded (for the particular baseused).

� To determine the volume of the mold:

The suppositories are carefully melted in a calibratedbeaker, and the volume of the melt is determined forthe total number as well as for the average of onesuppository.

Determination of the Amount of Base RequiredDetermination of the Amount of Base RequiredDetermination of the Amount of Base RequiredDetermination of the Amount of Base Required

Rx

Prepare 100mg

diclofenac sodium supps

using cocoa butter as the

base

no: 10 supp

Prescriptions

do not indicate

amount of the

base

The pharmacist calculates the

needed amount of the base

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3 mL base +

0.25 mL drug

Supp mold

V = 3 mL

Extra volume

results from drug

e.g. 0.25 mL

Plain base

Drug volume should

be deducted from

base volume:

3 - 0.25 = 2.75 mL

The weight of 0.25 mL drug should be calculated by

multiplying with density

Determination of the Amount of Base RequiredDetermination of the Amount of Base RequiredDetermination of the Amount of Base RequiredDetermination of the Amount of Base Required

� The determination of the amount of the base in thepreparation of medicated suppositories requires thefollowing steps:

(a) weigh the active ingredient for the preparation of asingle suppository;

(b) dissolve it or mix it (depending on its solubility in thebase) with a portion of melted base insufficient to fill onecavity of the mold, and add the mixture to a cavity;

(c) add melted base to the cavity to fill it completely;

(d) allow the suppository to congeal and harden; and

(e) remove the suppository from the mold and weigh it.The weight of the active ingredients subtracted from theweight of the suppository yields the weight of the base.This amount of base multiplied by the number ofsuppositories to be prepared in the mold is the totalamount of base required.

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� Volume of base= Total volume of the mold -the

volume of the drug substances

� If 12 ml of cocoa butter are required to fill a

suppository mold and if the medicaments in the

formula have a collective volume of 2.8 ml, how

many gram of cocoa butter required? (the density

of cocoa butter is 0.86 g/mL) v/d= wt

12-2,8= 9.2 ml / 0.86 gm/ml= 7.9 gm

Determination of the amount of base requiredDetermination of the amount of base required

Density Factor (DF) MethodDensity Factor (DF) MethodDensity Factor (DF) MethodDensity Factor (DF) Method

1. Determine the average blank weight (A) per moldusing the suppository base of interest.

2. Weigh the quantity of suppository base necessary for10 suppositories.

3. Weigh 1.0 g of medication. The weight of medicationper suppository (B) is equal to 1 g/10 supp = 0.1g/supp.

4. Melt the suppository base and incorporate themedication, mix, pour into molds, cool, trim, andremove from the molds.

5. Weigh the 10 suppositories and determine the averageweight (C).

6. Determine the density factor as follows:

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Density Factor (DF) MethodDensity Factor (DF) MethodDensity Factor (DF) MethodDensity Factor (DF) Method

Density Factor =B

(A+ B – C)A is the average weight of blank

B is the weight of medication per suppository

C is the average weight of medicated suppository

7. Take the weight of the medication required for each

suppository and divide by the density factor of the

medication to find the replacement value of the

suppository base.

8. Subtract this quantity from the blank suppository weight.

9. Multiply by the number of suppositories required to

obtain the quantity of base required for the prescription.

10. Multiply the weight of drug per suppository by the

number of suppositories required to obtain the quantity

of active drug required for the prescription.

Derivation of Density Factor EquationDerivation of Density Factor EquationDerivation of Density Factor EquationDerivation of Density Factor Equation

W of medicated supp = w of blank supp + w of drug – w of displaced base

C = A + B – X

DF value g of drug displace 1 g base

B g of drug displace X g base

X = B/DF

C = A + B – (B/DF)

B/DF = A + B – C

DF = B / (A + B – C)

Density Factor (DF) =B

A + B – C

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Example on How to Use Density FactorExample on How to Use Density FactorExample on How to Use Density FactorExample on How to Use Density Factor

Prepare 12 acetaminophen (B) 300 mg suppositoriesusing cocoa butter. The average weight of the cocoabutter blank (A) is 2 g and the average weight of themedicated suppository (C) is 2.1 g.

� From step 7: (0.3 g)/1.5 = 0.2 (the replacement valueof the base)

� From step 8: 2.0 g-0.2 g = 1.8 g

� From step 9: 12 x 1.8 g = 21.6g cocoa butter required

� From step 10: 12 x 0.3 g = 3.6 g acetaminophen

(DF) =0.3

= 1.52 – 2.1 + 0.3

Density Factor MethodDensity Factor MethodDensity Factor MethodDensity Factor Method

� It is generally assumed that if the quantity of active drugis less than 100 mg, then the volume occupied by thepowder is insignificant and need not be considered.This is usually based on a 2 gram suppository weight.Obviously, if a suppository mold of less than 2 grams isused, the powder volume may need to be considered.

� The density factors of various bases and drugs need tobe known to determine the proper weights of theingredients to be used. Density factors relative to cocoabutter have been determined. If the density factor of abase is not known, it is simply calculated as the ratio ofthe blank weight of the base and cocoa butter.

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Medicament DF value

Aminophylline 1.3

Aspirin 1.1

Bismuth subgallate 3.0

Castor oil 1.0

Chloral hydrate 1.5

Cinchocaine hydrochloride 1.0

Cocaine hydrochloride 1.4

Dimenhydrinate 1.3

Hamamelis dry extract 1.5

Hydrocortisone acetate 1.5

Icthammol 1.0

Morphine hydrochloride 1.6

Resorcinol 1.5

Zinc oxide 5.0

Examples of DF values for Some APIsExamples of DF values for Some APIsExamples of DF values for Some APIsExamples of DF values for Some APIs

Preparing and Pouring the MeltPreparing and Pouring the MeltPreparing and Pouring the MeltPreparing and Pouring the Melt

� Base melting: Using the least possible heat, the weighedsuppository base material is melted, generally over a water bath,since no great deal of heat is usually required.

� Drug incorporation: Medicinal substances are usuallyincorporated into a portion of the melted base by mixing on a glassor porcelain tile with a spatula. After incorporation, this material isstirred into the remaining base, which is allowed to cool almost toits congealing point. Any volatile materials or heat-labilesubstances should be incorporated at this point with thoroughstirring.

� Pouring:

� The melt is poured carefully and continuously into each cavity ofthe mold.

� If any undissolved or suspended materials in the mixture aredenser than the base, so that they have a tendency to settle,constant stirring, even during pouring, is required, else the lastfilled cavity will contain a disproportionate share of the undissolvedmaterials.

� The solid materials remain suspended if the pouring is performedjust above the congealing point and not when the base is too fluid.

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� If the melt is not near the congealing point when poured, the solidsmay settle within each cavity of the mold to reside at the tips of thesuppositories, with the result that the suppositories may be brokenwhen removed from the mold.

� Alternatively, a small quantity of silica gel (about 25 mg persuppository) can be incorporated into the formula to aid in keepingthe active drug suspended.

� In filling each suppository cavity, the pouring must be continuous toprevent layering, which may lead to a product easily broken onhandling.

� To ensure a completely filled mold upon congealing, the melt ispoured excessively over each opening, to prevent formation ofrecessed dips in the ends of the suppositories. Therefore an extraamount (extra 1-2 suppositories) of the base is added.

� When solidified, the excess material is evenly scraped off of the topof the mold with a spatula warmed by dipping into a beaker ofwarm water; this will make a smooth surface on the back of thesuppository during trimming.

� The mold is usually placed in the refrigerator to hastenhardening.

� Removing of suppositories: When the suppositories arehard, the mold is removed from the refrigerator andallowed to come to room temperature. Then the sectionsof the mold are separated, and the suppositories aredislodged, with pressure being exerted principally on theirends and only if needed on the tips.

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Preparation By CompressionPreparation By CompressionPreparation By CompressionPreparation By Compression

� Suppositories may be prepared by forcing the mixed mass of thebase and the medicaments into special molds using suppository-making machines. In preparation for compression into the molds,the base and the other formulative ingredients are combined bythorough mixing, the friction of the process softening the base intoa paste-like consistency.

� On a small scale, a mortar and pestle may be used. Heating themortar in warm water (then drying it) greatly facilitates the softeningof the base and the mixing.

� On a large scale, a similar process may be used, employingmechanical kneading mixers and a warm mixing vessel.

� Compression is especially suited for making suppositories thatcontain heat-labile medicinal substances or a great deal ofsubstances that are insoluble in the base. In contrast to themolding method, compression permits no likelihood of insolublematter settling during manufacture. The disadvantage tocompression is that the special suppository machine is requiredand there is some limitation as to shapes of suppositories that canbe made.

Vaginal suppositories (Vaginal suppositories (PessariesPessaries))Vaginal suppositories (Vaginal suppositories (PessariesPessaries))

� These preparations are employed principally to:

� Combat infections in the female genitourinary tract:Trichomonas vaginalis, Candida (Monilia) albicans or otherspecies, and Haemophilus vaginalis: nystatin,clotrimazole, butoconazole nitrate, terconazole, andmiconazole (antifungals) and triple sulfas, sulfanilamide,povidone iodine, clindamycin phosphate, metronidazole,and oxytetracycline (antibacterials).

� Restore the vaginal mucosa to its normal state:estrogenic substances such as dienestrol

� For contraception: nonoxynol-9, a spermicide

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� The most commonly used base for vaginal suppositoriesconsists of combinations of the various molecular weightpolyethylene glycols. To this base is frequently addedsurfactants and preservative agents, commonly theparabens.

� Many vaginal suppositories and other types of vaginaldosage forms are buffered to an acid pH, usually abutpH 4.5, which resembles that of the normal vagina.This acidity discourages pathogenic organisms andprovides a favorable environment eventual recolonizationby the acid-producing bacilli normally found in the vagina.

� The polyethylene glycol-based vaginal suppositoriesare water miscible and aregenerally sufficiently firm forthe patient to handle andinsert without great difficulty.However, to make the taskeasier, many manufacturersprovide plastic insertiondevices that are used to holdthe suppository or tablet forproper placement within thevagina.

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Vaginal InsertsVaginal InsertsVaginal InsertsVaginal Inserts

� vaginal inserts, or vaginal tablets are more widely usednowadays than are commercial vaginal suppositories;because tablets are easier to manufacture, morestable, and less messy.

� Vaginal tablets are usually ovoid and are accompanied intheir packaging with a plastic inserter, a device for easyplacement of the tablet within the vagina.

� Vaginal tablets contain the same types of anti-infectiveand hormonal substances as vaginal suppositories. Theyare prepared by tablet compression and are commonlyformulated to contain lactose as the base or filler, adisintegrating agent such as starch, a dispersing agentsuch as polyvinylpyrrolidone, and a tablet lubricant suchas magnesium stearate.

� The tablets are intended to disintegrate within the vagina,releasing their medication.

� Some vaginal inserts are capsules of gelatin containingmedication to be released intravaginally.

Quality ControlQuality ControlQuality ControlQuality Control

Quality control procedures listed in the USP for manufacturedsuppositories include:

� The appearance (surface texture and shape).

� Odour and colour.

� Actual weight and weight variation.

� The mechanical strength ( can be tested in several ways,

including a tablet-crushing strength tester).

� Content uniformity.

� Disintegration

� In vitro dissolution test

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Packaging & StoragePackaging & StoragePackaging & StoragePackaging & Storage

� Glycerin suppositories and glycerinated gelatin suppositories arepackaged in tightly closed glass containers to prevent a change inmoisture content.

� Suppositories stored in high humidity may absorb moisture andtend to become spongy, whereas suppositories stored in places ofextreme dryness may lose moisture and become brittle.

� Cocoa butter Suppositories are individually wrapped or otherwiseseparated in compartmented boxes to prevent contact andadhesion.

� Suppositories containing light-sensitive drugs are individuallywrapped in an opaque material such as a metallic foil. In fact,most commercial suppositories are individually wrapped in eitherfoil or plastic. Some are packaged in a continuous strip, separatedby tearing along perforations. Suppositories are also commonlypackaged in slide boxes or in plastic boxes.

� Since suppositories are adversely affected by heat, it is necessaryto maintain them in a cool place. Cocoa butter suppositories mustbe stored below 30°C, and preferably in a refrigerator (2-8°C).Glycerinated gelatin suppositories can be stored at controlledroom temperature (20-25°C). Suppositories made from a base ofpolyethylene glycol may be stored at usual room temperatures.

Use and Storage InstructionsUse and Storage InstructionsUse and Storage InstructionsUse and Storage Instructions

� If they must be stored in the refrigerator, suppositoriesshould be allowed to warm to room temperature beforeinsertion.

� Cocoa butter suppositories should be rubbed gently withthe fingers to melt the surface to provide lubrication forinsertion.

� Glycerinated gelatin or polyethylene glycol suppositoriesshould be moistened with water to enhance lubrication.

� If the polyethylene glycol suppository formulation does notcontain at least 20% water, dipping it into water just priorto insertion prevents moisture from being drawn fromrectal tissues and decreases irritation.

� Bullet-shaped rectal suppositories should be insertedpointed end first.

� The patient who is to use half of a suppository should betold to cut the suppository lengthwise with a clean razorblade.