suppositories Flashcards
Suppositories
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)
Application of suppositories
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.
When are suppositories recommended
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)
Advantage of suppositories
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
Disadvantage of suppositories
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
desirable properties of suppositories
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
Melting range of suppository
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.
types of bases for suppository
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
Oleaginous bases
Oleaginous bases
Also known as oily or fatty bases
Examples:
theobroma oil
hydrogenated fatty acids of vegetable oils
monoglycerides of high MW fatty acids
Solidification of bases shld
During solidification a suppository should exhibit enough volume contraction to permit removal from the mould or plastic former
Theobroma oil
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.
Disadvantage of theobroma oil base and the alternative
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
substances that can soften theobroma oil
volatile oils,
phenol
chloral hydrate
Add what to theobroma oil to prevent softening
beewax
how to prevent theobroma oil from sticking on the mould
lubricating with soap solution (NOT OIL)
Water soluble or water miscible bases
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
Glycerinated gelatin
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
Function of gelatin
Gelatin –> hardness (more rigid and longer acting)
types of gelatin
There are two types of gelatin:
Pharmagel A: Cationic and incompatible with anionic compounds
Pharmagel B: Anionic and incompatible with cationic compounds
function of glycering
glycerin –> hydrophilicity (so base can dissolve, can
incorporate hydrophile drug /
aq soln)
Advantage of glycerinated gelatin base
More prolonged drug release
—> Commonly used in pessaries
More easily inserted
–> Suitable for urethral administration
Disadvantage of glycerinated gelatin base
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
Polyethylene glycols
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
characteristic
PEG 1000 96%
PEG 4000 4%
Base is soft and disintegrate rapidly
Characteristic
PEG 1000 75%
PEG 4000 25%
Base is harder and gives a slower drug release
Characteristic
PEG 1540 70%
PEG 6000 30%
base is much harder and can be used for drugs that lower the melting of the base
Characteristic
PEG 1540 30%
PEG 6000 60%
water 10%
Base includes water and is suitable for water soluble drug
PEG 6000 w PEG 1500
VS
PEG 1500
PEG 6000 w PEG 1500 have longer disintegration time
BUT is more brittle.
Advantage of PEG bases
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
Disadvantage of PEG bases
Incompatible with phenols
Hygroscopic (drug that is prone to hydrolysis -= not
good)
Emulsifying bases
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)
Advantage of emulsifing bases
Not adversely affected by overheating
Solidify rapidly at room temperature
Do not adhere to mould
Non-irritating
preparation of suppositories
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
Hot process
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
Cold process
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)
Packaging of suppositories
Partitioned boxes
Screw-capped glass or plastic containers Aluminium foil wrappings
Disposable plastic moulds
Storage condition
Store suppositories in a cool and dry place Theobroma oil (< 30C)
Glycerinated gelatin (< 35 C)
PEGs (
shelf life of suppositories
~ 2 years
potential problems on storage
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
Evauation of suppositories
Appearance Uniformity of weight* Uniformity of drug content # Disintegration time* Drug release profile # Mechanical strength Melting behaviour
*BP requirement
Appearance
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
Uniformity of weight
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
Uniformity of drug content
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.
Disintegation time
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
Interpretation of results for disintegration time
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
Drug release profile
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
Mechanical strength
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.
Melting behaviour
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)
Drug release how
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
Physicochemical factors of suppositories which affect the release and bioavailability of drugs
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)
