suppositories

Question 1

Suppositories

Answer 1

Suppositories are solid dosage forms intended for insertion into body orifices (other than oral cavity) where they melt, soften or dissolve and exert localized or systemic effects

typically cylindrical with one or both ends tapered (1-2g)

Question 2

Application of suppositories

Answer 2

1) carry drug for action at site of placement
E.g. emollients, astringents, antiseptics, local anaesthetics

2) Carry drug for systemic action
E.g. hypnotics, tranquilizers, antispasmodics, antipyretic, antiemetic

Suppositories are however primarily intended for treatment of constipation and haemorrhoids.

Question 3

When are suppositories recommended

Answer 3

1) if person cannot swallow (eg vomit, child, elder,
unconscious).
2) Drug which are less suitable for oral administration.
(eg gastric discomfort, drug break down in GIT)

Question 4

Advantage of suppositories

Answer 4

1) safe and painless
2) good for drug labile to GIT
3) Hepatic first pass elimination of high CL drug is
partially avoided
4) Small and large doses can be administered
5) Drug release profile can be controlled
6) LTC patients eg elder
7) Child
8) Simple administration
9) useful for pt who are N/V

Question 5

Disadvantage of suppositories

Answer 5

1) strong feeling of aversion
2) slow onset (~30mins) and incomplete drug
adsorption
3) considerable intersubject and intrasubject variation
4) development of proctitis (inflammation of rectum)
5) Leakage

Question 6

desirable properties of suppositories

Answer 6

1) Can be moulded by pouring or compression
2) Does not adhere to the mould
3) Stable if heated above its melting point
4) Compatible with drug
5) Non-toxic and non-irritating
6) Stable during storage
7) Releases drug at the desired rate
8) Does not leak out of orifice into which it is inserted
9) Keeps its shape when handled and easy to insert

Question 7

Melting range of suppository

Answer 7

The melting range should be small enough to give rapid solidification after preparation, thus preventing agglomeration or sedimentation of suspended drug particles.

When the solidification rate is high, eg, rapid cooling is applied –> fissures in the suppository

The melting range should be sufficiently wide to permit easy preparation.

Question 8

types of bases for suppository

Answer 8

1) Oleaginous bases
E.g. Fats and oils

2) Water-soluble or water-miscible bases
E.g. Glycerinated gelatin, PEGs

3) Emulsifying bases ( NOT EMULSION BASE)
E.g. Witepsol, Massupols

Question 9

Oleaginous bases

Answer 9

Oleaginous bases
Also known as oily or fatty bases
Examples:
theobroma oil
hydrogenated fatty acids of vegetable oils
monoglycerides of high MW fatty acids

Question 10

Solidification of bases shld

Answer 10

During solidification a suppository should exhibit enough volume contraction to permit removal from the mould or plastic former

Question 11

Theobroma oil

Answer 11

1) oleaginous base
Also known as cocoa butter
Vegetable fat extracted from seeds of the cacao fruit (Theobroma Cacao)
It is composed of triglycerides of mainly oleic, stearic and palmitic acids
It occurs in three crystalline forms:
 ALPHA- Unstable; melting point of 22-24 ºC
 BETA - Stable; melting point of 34-36 ºC
 GAMMA - Unstable; melting point of 18 ºC

The use of low heat (40 to 50 ºC) and slow cooling are crucial for direct recrystallization to the BETA -crystals

Rapid cooling can cause suppositories to become brittle.

Question 12

Disadvantage of theobroma oil base and the alternative

Answer 12

Melting process must be carefully monitored Theobroma oil tends to stick to the sides of the mould
Theobroma oil tends to soften in tropical climate and when substances such as volatile oils, phenol or chloral hydrate are added
These suppositories are more difficult to administer as theobroma oil melts on the finger tip
Theobroma oil tends to leak out of the orifice

Alternatives: Fattibase, Suppocire

Question 13

substances that can soften theobroma oil

Answer 13

volatile oils,
phenol
chloral hydrate

Question 14

Add what to theobroma oil to prevent softening

Answer 14

beewax

Question 15

how to prevent theobroma oil from sticking on the mould

Answer 15

lubricating with soap solution (NOT OIL)

Question 16

Water soluble or water miscible bases

Answer 16

These bases do not melt but dissolve slowly in the biological fluid
They are commonly prepared from glycerinated gelatin or polyethylene glycols

good for slow release

Question 17

Glycerinated gelatin

Answer 17

Water soluble or water miscible bases

BP formula :
4 -18% gelatin + 70% glycerin + 12 -26 % water

USP formula :
20% gelatin + 70% glycerin + 30% water

Gelatin –> hardness (more rigid and longer acting)
glycerin –> hydrophilicity (so base can dissolve, can
incorporate hydrophile drug /
aq soln)

There are two types of gelatin:
Pharmagel A: Cationic and incompatible with anionic compounds
Pharmagel B: Anionic and incompatible with cationic compounds

Question 18

Function of gelatin

Answer 18

Gelatin –> hardness (more rigid and longer acting)

Question 19

types of gelatin

Answer 19

There are two types of gelatin:
Pharmagel A: Cationic and incompatible with anionic compounds
Pharmagel B: Anionic and incompatible with cationic compounds

Question 20

function of glycering

Answer 20

glycerin –> hydrophilicity (so base can dissolve, can
incorporate hydrophile drug /
aq soln)

Question 21

Advantage of glycerinated gelatin base

Answer 21

More prolonged drug release
—> Commonly used in pessaries

More easily inserted
–> Suitable for urethral administration

Question 22

Disadvantage of glycerinated gelatin base

Answer 22

1) Hygroscopic (tend to absorb moisture)
–> Dehydrating effect on mucous membrane
(attract water from biological membrane giving rise to stinging sensation)
Prevent by moistening the suppositories

2) Support growth of mould

Question 23

Polyethylene glycols

Answer 23

water soluble or water miscible bases
Also known as carbowaxes
General chemical formula: HOCH2(CH2OCH2)nCH2OH

A combination of PEGs (Macrogol) is often employed to obtain a base of desired hardness, melting point and water solubility

PEG less than 1000MW = liquid
more than 1500 MW = solid
1000 - 1500 MW = semi solid

Question 24

characteristic
PEG 1000 96%
PEG 4000 4%

Answer 24

Base is soft and disintegrate rapidly

Question 25

Characteristic
PEG 1000 75%
PEG 4000 25%

Answer 25

Base is harder and gives a slower drug release

Question 26

Characteristic
PEG 1540 70%
PEG 6000 30%

Answer 26

base is much harder and can be used for drugs that lower the melting of the base

Question 27

Characteristic
PEG 1540 30%
PEG 6000 60%
water 10%

Answer 27

Base includes water and is suitable for water soluble drug

Question 28

PEG 6000 w PEG 1500
VS
PEG 1500

Answer 28

PEG 6000 w PEG 1500 have longer disintegration time

BUT is more brittle.

Question 29

Advantage of PEG bases

Answer 29

Bases with higher melting point can be formulated Convenient storage
Easy insertion
No leakage from orifice
Bases of varying solubilities can be formulated Control of drug release

Question 30

Disadvantage of PEG bases

Answer 30

 Incompatible with phenols
 Hygroscopic (drug that is prone to hydrolysis -= not
good)

Question 31

Emulsifying bases

Answer 31

These are usually composed of triglycerides with one or more emulsifying agents (EA allow base to dissolve)

Witepsol: Hydrogenated triglycerides of lauric acid with added monoglycerides (EA)

Massupol : Glyceryl esters, chiefly lauric acid, with added glyceryl monostearate (EA)

higher MP than theobroma oil.
For sustained release

Does not melt straight away
get soften first
disintegrate
disperse (help emulsify fatty substance in the aq biological matrix)

Question 32

Advantage of emulsifing bases

Answer 32

Not adversely affected by overheating
Solidify rapidly at room temperature
Do not adhere to mould
Non-irritating

Question 33

preparation of suppositories

Answer 33

1) Hot process
Fusion or melt moulding
This process employs heat and is unsuitable for thermolabile drugs
It is more commonly employed than cold process

2) Cold process
Hand moulding or compression moulding
This process does not employ heat and is suitable for thermolabile drugs

Question 34

Hot process

Answer 34

1) Base is melted over a hot water-bath. Drug is dissolved or dispersed in the molten base
2) Molten mixture is poured into lubricated mould and allowed to set in the cold
3) The suppositories formed are removed from the metal moulds or supplied in the disposable moulds

The mould is made of metal (reusable) or plastic (disposable)
The condition of the metal mould is important (DONT MIX MOULD)

Lubrication of OB = use soap
Lubrication of water soluble base = use OIL

Question 35

Cold process

Answer 35

1) Hand moulding
A slow process suitable for small scale production only
The base is thoroughly kneaded with the drug, rolled into a thin cylinder of uniform diameter and cut into individual pieces which are hand moulded to the desired shape

OR

2) Compression moulding
Partially automated and relatively faster than hand moulding
(can trap air inside suppositories therefore underweight)

Question 36

Packaging of suppositories

Answer 36

Partitioned boxes
Screw-capped glass or plastic containers Aluminium foil wrappings
Disposable plastic moulds

Question 37

Storage condition

Answer 37

Store suppositories in a cool and dry place Theobroma oil (< 30C)
Glycerinated gelatin (< 35 C)
PEGs (

Question 38

shelf life of suppositories

Answer 38

~ 2 years

Question 39

potential problems on storage

Answer 39

theobroma oil –> bloom
Fat base –> elevated melting point

Bloom is due to temperature flatuation –> whitish deposit (bloom) on suppositories. Theobroma oil become unstable and migrate to surface and then converted to more stable form.

Elevated melting point is due to conversion of less stable crystalline form of base to a more stable form.
OB release drug by melting thus an increase in elevated melting point can lead to slower release of drug

Question 40

Evauation of suppositories

Answer 40

Appearance 
Uniformity of weight* 
Uniformity of drug content # 
Disintegration time* 
Drug release profile # 
Mechanical strength 
Melting behaviour

*BP requirement

Question 41

Appearance

Answer 41

This includes internal and external appearance
Colour
Surface condition (Smooth? Cracks? Pits?)
Shape (Conical? Distorted?)
Uniformity of mix (Homogeneous?) = look at interior
after slicing lengthwise

The suppository is sliced lengthwise for examination of internal appearance

Question 42

Uniformity of weight

Answer 42

This reflects the uniformity of drug content
BP method
1)Take 20 suppositories at random from the batch 2)Weigh these suppositories individually
3)Calculate their average weight

Acceptance criteria:

a) Not more than 2 of the individual weights deviate from the average weight by more than 5%, AND
b) None deviates by more than 10%

This test is not required for moulded suppositories that are required to comply with the test for uniformity of drug content

Question 43

Uniformity of drug content

Answer 43

The test for uniformity of drug content is prescribed for specific suppositories
The drug is extracted from the base and assayed using appropriate methods (spectrophotometric method)
Suppositories that need to comply with this test do not have to undergo the test for uniformity of weight

Water soluble base = dissociate the suppository in water then assay

OB = melt suppositories then extract using solvent that dont dissolve the base but drug is solube in it.

Question 44

Disintegation time

Answer 44

Disintegration time affects the rate of drug release The disintegration test determines whether the suppositories disintegrate or soften within a prescribed time when placed in a liquid medium under prescribed experimental conditions

disintegration medium is distilled water

Apparatus = metal device comprising two perforated metal discs separated by a distance of 3 cm.
(39holes)

This apparatus is put in a vessel containing at least 4 litres of water at 36C to 37C and fitted with a slow stirrer

The apparatus is inverted every 10 minutes in the liquid medium (prevent suppositories from sitting at location for too long as it may affect dissolution)

The disintegration test is carried out on 3 suppositories separately

Question 45

Interpretation of results for disintegration time

Answer 45

Disintegration is complete when the suppository satisfies any one of the following three criteria:
1) Suppository is completely dissolved
2) Suppository has dispersed into its component parts
( For OB/fat base, molten theobroma oil float to top)
3) Suppository has become soft and the mass has no solid core offering resistance to pressure with a glass rod

Acceptance criteria
Fat-based Disintegration time = <30 min
Water-solubleDisintegration time = <60 min
therefore fat base will release drug faster

Question 46

Drug release profile

Answer 46

This is obtained by determining the amount of drug released from the suppository to the external medium over time
Aliquot samples of dissolution medium withdrawn at specific time intervals for drug assay

Dissolution tests using the following apparatus are usually employed:
Dissolution Apparatus 1 (Basket method)
Dissolution Apparatus 2 (Paddle method) using a dialysis membrane

both prevent suppository from floating to the top.

Can use any of the 2 methods
just on graph, Basket method will have faster release profile than paddle method.
Coz basket method has porous hold while paddle method uses semi-permeable membrane.

Temperature used is 37 +/- C

Question 47

Mechanical strength

Answer 47

The suppository should be strong enough to withstand the rigours of normal handling
The strength of the suppository is determined with the aid of an apparatus

Initial weight of device = 600g
individual weight = 200g

every minute new weight is added.

1) if rupture within 20 sec = dont count added wt
2) if rupture between 20-40sec = wt divided by 2
3) rupture after 40 sec = add newly added wt

remember to include initial 600g of device.

Question 48

Melting behaviour

Answer 48

For oleaginous base only

Softening temperature
Temperature at which deformation occurs
It indicates ease of insertion and physical stability of suppository during handling

Liquefaction temperature
Temperature at which suppository melts
It affects drug release
This test is necessary only for suppositories with oleaginous base

Suppositories place in the glass tube with constriction in the middle.
glass rod, rubber tube and lead cylindrical weight rest on suppositories.

when temp rises, suppositories will soften and the lead cylindrical weight will drop onto the rest. (softening temp)

when temp rises further suppositories will melt and flow out thru the middle constriction. and the glass rod will drop (liquefaction temp)

Question 49

Drug release how

Answer 49

OB
insert into rectum –> base melt and spreads on mucous lining –> drug particle sediment to the mucous membrane –> wetting –> dissolution

Water soluble base
insert into rectum –> dissolve –> sedimentation –> wetting –> dissolution

Question 50

Physicochemical factors of suppositories which affect the release and bioavailability of drugs

Answer 50

Chemical composition of base

• OB fastest release; F higher
  
  • -> WSB –> emulsifying base (slow)

Viscosity of base
Viscosity up = slower release ; F drop

Interaction between base and drug
Interaction up = release rate drop

Partition coefficient of drug between base and rectal
fluid ( partition into base = less drug in fluid;
absorption rate drop)
Drug particle size (bigger = faster sedimentation but
slower dissolution
Charges on drug molecules ( neutral = F up, absorb
up)
Lipid solubility of drug (lipophilic = F up more
peameable)
Surface property of drug
(wettability up = F up)
Amount of drug
(amt up = absorption up)

Any effect of suppository on rectum/mucous
membrane (irritation = out of body = F drop)