1
Q
What is the definition of suppositories?
A
- Solid dosage forms intended for insertion into body orifices (other than oral cavity) where they melt, soften, or dissolve and exert localised/systemic effects
- various shapes and sizes
- different names depending on the body orifice in which they are inserted
2
Q
What are the different names for suppositories?
A
- Suppository
- Pessary
- Urethral bougie
- Nasal bougie
- Ear cone
3
Q
What is the description for suppository?
A
- Rectal adm
- cylindrical with one/both ends tapered
- 1 or 2g
4
Q
What is the description for pessary?
A
- Vaginal adm
- Oviform, cone-shaped
- 4 or 8g
5
Q
Why suppositories are used? what are its applications?
A
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
6
Q
What are the desirable properties of a suppository base? (there are 9 of them)
A
- can be moulded by pouring or compression
- stable if heated above its melting point
- does not adhere to the mould
- releases drug at the desired rate
- keeps its shape when handled and easy to insert
- does not leak out of orifice into which it is inserted
- stable during storage
- non-toxic and non-irritating
- compatible with drug
7
Q
when are suppositories recommended for drug delivery in some situations?
A
- for pts unable to make use of oral route of drug adm (unconscious, severe N/V, can’t take anything oral)
- for drugs which are less suited for oral adm (drug degrade under GIT conditions, cause GIT irritation, drugs unpleasant, drugs degrade by transportation of liver portal circulation)
8
Q
what types of bases can be used for suppositories?
A
- oleaginous bases (e.g. fats and oils)
- water-soluble / water-miscible bases (glycerinated gelatin, PEGs)
- emulsifying bases (e.g. Witepsol, Massupol)
9
Q
What are some oleaginous bases used in suppositories?
A
- oily and fatty bases
- theobroma oil
- hydrogenated fatty acids of vegetable oils
- monoglycerides of high MW fatty acids
10
Q
What is theobroma oil composed of? (note: it is an oleaginous base)
A
- cocoa butter
- vegetable fat extracted form seeds of theobroma cacao fruit
- composed of triglycerides of mainly oleic, stearic and palmitic acids
11
Q
What are the 3 crystalline forms for theobroma oil? and its stability and melting points?
A
alpha - unstable (mp 22-24oC)
beta - stable (34-36oC)
gamma - unstable (18oC)
12
Q
how to prepare beta crystals?
A
use of low heat (40-50oC) and slow cooling are crucial for direct recrystallisation to the beta-crystals
13
Q
What are the disadvantages of using theobroma oil? (there are 5)
(reminder: it is an oleaginous base)
A
- Melting process must be carefully monitored
- Tends to stick to sides of mould
- Tends to soften in tropical climate and soften when substances such as volatile oils, phenol or chloral hydrate are added
- more difficult to adm suppositories as theobroma oil melts on finger tip
- theobroma oil tends to leak out of the orifice
14
Q
Why are water-soluble / water-miscible bases used in suppositories? Examples of such bases?
A
- don’t melt but dissolve slowly in biological fluid (rectal fluid)
- commonly prepared from glycerinated gelatin GG or PEGs
15
Q
What does glycerinated gelatin composed of?
A
BP formula: 4-18% gelatin, 70% glycerin + 12-26% water (higher conc of water)
USP formula: 20% gelatin + 70% glycerin + 10% water (more harder due to higher conc of gelatin)
16
Q
When are glycerinated gelatin used? (Applications)
A
- Antiseptic
- for pessaries (for vaginal infection, slow release)
17
Q
Functions of the ingredients in glycerinated gelatin?
A
- gelatin –> hardness (responsible for solid state of base)
- glycerin –> hydrophilicity (base can attract water to base)
18
Q
What are the 2 types of gelatin?
A
Pharmagel A: Cationic and incompatible with anionic compounds
Pharmagel B: Anionic and incompatible with cationic compounds
19
Q
What are the advantages of glycerinated gelatin base? (there are 2)
A
- More prolonged drug release (commonly used in pessaries)
2. More easily inserted (suitable for urethral adm) (doesn’t melt on fingertup, due to hardness, easier to insert)
20
Q
What are the disadvantages of glycerinated gelatin (GG) base? (there are 2)
A
- Hygroscopic (dehydrating effect on mucous memb) - stinging sensation when supp composed of GG adm into rectum/vagina/urethra. To prevent this, moisten supp with water before adm
- support growth of mould - ensure hygienically prepared and properly stored
21
Q
What are PEGs?
A
- carbowaxes
- MW <400: typically liquid
- MW >3000: are solids
- combination of PEGs (macrogol) is often employed to obtain a base of desired hardness, m.p., and water solubility
22
Q
What is the characterisitic for composition of:
PEG 1000 96%
PEG 4000 4%
A
Base is soft and disintegrates rapidly
23
Q
What is the characterisitic for composition of:
PEG 1000 75%
PEG 4000 25%
A
Base is harder and gives a slower drug release
24
Q
What is the characterisitic for composition of:
PEG 1540 70%
PEG 6000 30%
A
Base is much harder and can be used for drugs that lower the mp of the base
25
What is the characterisitic for composition of:
PEG 1540 30%
PEG 6000 60%
Water 10%
Base includes water and is suitable for water-soluble drugs
| Possible to dissolve drug in water and then incorporated with PEGs during heating
26
What are the advantages of PEG bases? (there are 4)
1. Bases with higher mp can be formulated
a) convenient storage
b) easy insertion
c) no leakage from orifice
2. Bases of varying solubilities can be formulated
d) control of drug release
27
What are the disadvantages of PEG bases?
1. Incompatible with phenols
| 2. Hygroscopic
28
What does emulsifying bases composed of?
TGs with one or more emulsifying agents e.g. witepsol or massupol
29
What does witepsol consist of?
Hydrogenated TGs of lauric acid with
added monoglycerides (makes the base emulsifying)
30
What does massupol comprises of?
Glyceryl esters, chiefly lauric acid, with
added glyceryl monostearate (makes the base emulsifying)
31
What are the advantages of emulsifying bases? (there are 4)
1. Not adversely affected by overheating
2. Solidify rapidly at room temp
3. Do not adhere to mould
4. Non-irritating
32
What are the disadvantages of emulsifying bases?
1. not useful for certain conditions where the base needs to be released quickly e.g. Pain
In this case; Theobroma (is preferred for immediate relief) melt faster and facilitates the release of the drug
2. Rectal fluid: 1-3ml volume; volume available for the water soluble bases is small --> thus dissolve at slow rate and drug release slower
3. Emulsifying bases is even slower (Theobroma faster compared to glycerinated bases/PEGs)
4. emulsifying agents that is incorporated can attract some water into the base and slowly bring about emulsification of the base in the rectal fluid --> hygroscopic
33
How to prepare supp by hot process?
- Fusion or melt moulding
- employs heat and is unsuitable for thermolabile drugs
- more commonly employed than cold process
34
How to prepare supp by cold process?
- Hand moulding or compression moulding
| - Doesn't employ heat and is suitable for thermolabile drugs
35
What are the 3 steps of 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. Supp formed are removed from the metal moulds or supplied in the disposable moulds.
Mould made of metal (reusable) or plasticc (disposable)
Condition of the metal mould is impt (ensure have a smooth surface)
36
How is hand moulding (cold process) done?
- Slow process suitable for small scale production only
- 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
(like pasta)
37
How is compression moulding (cold process) done?
Partially automated and relatively faster than hand moulding
38
What is the disadvantage of compression moulding?
Disadvantages: Entrapment of air in mould - underweight suppositories
39
What are the types of packaging?
- Partitioned boxes
- Screw-capped glass or plastic containers
- Aluminium foil wrappings
- Disposable plastic moulds
Do not dispense in containers if suppositories have tendency to stick to one another
40
What are the storage conditions for suppositories?
- Cool and dry place
Theobroma oil (<30oC)
GG (<35oC)
PEG (can store at room temp, even up to 40oC)
stable for at least 2 years
41
What are the potential problems on storage of supp?
Theobroma oil - bloom
White powdery deposit on suppositories --> effect of temp fluctuation --> form unstable forms of theobroma found on surfaces (alpha and gamma); BUT suppositories can still be used
Fat base - elevated m.p.
Slow appearance of some stable forms of the base --> Affect rate of drug release from the base. Fat bases can also form crystalline forms and crystalline forms have higher m.p.
42
What are the evaluation of suppositories?
1. appearance
2. uniformity of weight*
3. uniformity of drug content#1
4. disintegration time*
5. drug release profile#2
6. mechanical strength
7. melting behaviour
* BP required
#1 don't need to do uniformity of weight if you do uniformity of drug content
#2 don't need to do disintegration time if you do drug release profile
43
What do we take note for appearance of supp (evaluation)?
- internal and external
- colour; Any unusual colour
- surface condition; Smooth or pitted
- shape; Conical or distorted
- uniformity of mix (homogeneous)
Supp is sliced *lengthwise* for examination of internal appearance
44
What do we take note for uniformity of weight of supp (evaluation)?
- reflects uniformity of drug content
- BP method:
1) take 20 supp at random from the batch
2) weigh these supp individually
3) calculate their avg weight
Acceptance:
a) not more than 2 of the individual weights deviate from the avg wt by more than 5% and
b) none deviates by more than 10%
Test not required for moulded supp that are required to comply with test for uniformity of drug content
45
What do we take note for uniformity of drug content of supp (evaluation)?
- for specific supp (more tedious; drugs that are highly potent)
- drug is extracted from base and assayed using appropriate methods
- Supp that need to comply with this test DO NOT have to undergo test for uniformity of weight
46
What do we take note for disintegration time (evaluation)?
- disintegration time affected rate of drug release
- determines whether the supp disintegrate or soften within a prescribed time when placed in a liquid medium under prescribed experimental conditions
- BP method:
water is the disintegration medium
Apparatus is put in a vessel at least 4L of water maintained at 36-37oC and fitted with a slow stirrer
Apparatus inverted every 10min in the liquid medium
Test carried out on 3 supp separately
47
How do we interpret the disintegration results?
disintegration complete when supp satisfies any ONE of the following 3 criteria:
1. supp is completely dissolved
2. supp has dispersed into its component parts
3. supp has become soft and the mass has no solid core offering resistance to pressure with a glass rod
Acceptance criteria:
Fat-based: =< 30min
Water-soluble: =< 60min
To pass the disintegration test, all 3 supp should satisfy the criteria
48
What do we take note for drug release profile (evaluation)?
- determine amt of drug released from the supp to external medium over time
Dissolution Apparatus 1 (Basket method) OR
Dissolution Apparatus 2 (Paddle method) using dialysis memb
Recommended for specific supp; e.g. Supp that are claimed to produce specific drug release profile
These supp determination is required; NO need to conduct the disintegration test
49
What do we take note for mechanical strength (evaluation)?
- strong enough to withstand the rigours of normal handling
- strength of supp determined with aid of apparatus
The weight on the frame exerted on the supp
Indicated by total number of the 200g weights + weight of frame (600g) = amt required to crush the supp
More weight used, stronger the mechanical strength of the supp
50
What do we take note for melting behaviour (evaluation)?
- Softening temp
~ temp at which deformation occurs
~ indicates ease of insertion and physical stability of supp during handling
- Liquefaction temp
~ temp at which supp melts
~ affects drug release
~ test is necessary ONLY for supp with oleaginous base
Temp is inc gradually
At certain temp; the weight will drop onto the rest --> supp is soften and deformed --> corresponding temp is the softening temp
51
How inserting supp into rectum results in a chain of effects leading to the bioavailability of drug? What are the chain of effects?
1. Oleaginous base with drug particles insert into rectum
2. Base melts and spread on mucous lining
3. Sedimentation onto mucous lining
4. Wetting by biological fluids on mucous lining
5. Dissolution: Diffusion of drug molecules through mucus lining
Solid cannot diffuse through
Solid would have to dissolve in the liquid medium and the solid molecules will diffuse into mucus lining
52
What are the physicochemical factors of supp which affect the release and F of drugs? (there are 10)
1. chemical compositions of base: Oleaginous base - fast release, Water miscible base - slow release, emulsifying - slowest drug release
2. Viscosity of base: Decrease viscosity of molten base -> increase the spreading onto the mucous lining -> more drug available for absorption
3. Interaction btw base and drug: Inc interaction; Dec conc of drug available for abs
4. Partition coefficient of drug btw base and rectal tissue: Inc in partition coeff; will dec tendency of drug to leve the base and thus this will dec the conc of drug available for abs
5. Drug particle size: MW; inc MW size will dec extent of spreading of particles also dec dissolution rate and collectively and dec rate of drug abs
6. Charges on drug molecules: Charges: memb lines rectum has more lipophilic characteristic; more difficult fo charged molecules to penetrate the memb
Drug should ave lipid solubility to penetrate the memb
7. Lipid solubility of drug
8. Surface property of drug: Surface pprty: greater wettability exhibit greater dissolution l thus abs by memb and inc amt of soluble drug inc rate of drug abs
Drug conc serves as driving force for drug diffusion and thus drug abs
9. Amouont of drug
10. Any effect of supp on rectal tissue: Irritant effect on rectum may cause expulsion of supp and drug not available to rectum
VS if supp has any surfactant, inc permeability of memb and this can inc drug abs
53
Important considerations in the formulation of supp - properties of the base (there are 8)
1. Stability: Some may undergo oxidation/hydrolysis/changes in physical state
Base should be stable so can play fn as drug carrier or to modify the drug release from supp for abs
2. Compatibility with other components: If base is incompatibility; fn of other components or base will be affected
3. Viscosity: For viscosity of molten bases; all types of bases
Manufacturer of supp; heating is applied; n of base in liquid form or metled can affect drug abs; n of molten base can also affect the production of supp
Affect sedimentation rate of solid drug particles that is dispense from the vessels to the moulds affected
Less n molten base - faster sedimentation rate in the vessel --> RESULT --> non-uniform distribution of drug particles in the base --> production of supp w variable drug content
4. Rate of drug release: optimal therapeutic outcome (fast or slow release)
5. Temp range btw melting and solidification: If range too small; molten base greater tendency to solidify during the manufacture; affect ease of manufacture
6. Volume of contraction: Contraction on cooling; prevent adhesion of solidify base to the mould
7. Brittleness: is it break easily when used/inserted
8. Hygroscopicity: Ideally NOT be hygroscopic; tendency to attract water --> water may affect stability of drugs that are sensitive to drug --> degradation by hydrolysis
If base is hygroscopic; attract water from mucous lining when inserted into rectum --> dehydrating effect --> stinging sensation
54
Important considerations in the formulation of supp - properties of the drug (there are 5)
1. Solubility
2. Particle size
3. Surface property
4. Amount in base
5. Displacement value: Determine amt of drug and base needed to produce the supp
55
What is the displacement value of drug?
- Number of part by weight of a drug which displaces one part by weight of the base
- Must be considered in calculation of amt of base required for a supp if the drug content is expressed in terms of weight
If drug content is expressed in terms of weight
If in % ; no need to consider displacement value
If 1g ; displacement value to be considered in the production
56
disadvantages of suppositories as a drug delivery
- strong feeling of aversion (mindset)
- supps can leak
- slow onset (~30min) and incomplete drug absorption
- intersubject and intrasubject variation in terms of drug absorption
- development of proctitis (inflammation of the tissue lining; discomfort and pain)
57
how to overcome the disadvantages of using theobroma oil as the oleaginous base? (2 alternatives)
Fattibase
Suppocire
Solid
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