1
Q
what are suppositories?
A
solid dosage forms intended for insertion into body orifices (Other than oral cavity) –> melt, soften/dissolve and exert localised/systemic effects –> various shape and sizes
2
Q
what are the types of suppositories available?
A
- suppository
- pessary
- urethral bougie
- nasal bougie
- ear cone
3
Q
What are some applications of suppositories?
A
- Carry drug for action at site of placement
- Carry drug for systemic action
- Recommended for drug delivery in patients unable to make use of oral route of drug administration and for drugs less suited for oral administration
4
Q
Disadvantages of suppositories as a drug delivery system:
A
- Strong feeling of aversion
- Suppositories can leak due to the type of base used, affecting drug treatment –> patient needs to lie down to prevent suppositories from dropping out
- Considerable intersubject and intrasubject variation
- development of prostatitis if used long term
- Possible slow onset and incomplete drug absorption
5
Q
Desirable properties of suppository bases:
A
- Can be moulded by pouring/compression
- Stable if heated above melting point
- Does not adhere to mould
- Releases drug at desired rate
- Keeps shape when handled and easy to insert
- Does not leak out of orifice into which it is inserted
- Stable during storage
- non-toxic, non-irritating
- compatible with drug
6
Q
What are the three crystalline forms of Theobroma oil?
A
- alpha: unstable and melting point of 22-24
- beta: stable, melting point of 34-36
- gamma: unstable, melting point of 18
7
Q
Disadvantages of theobroma oil base:
A
- Melting process needs to be carefully monitored
- Tends to stick to sides of the mould
- Tends to soften in tropical climate and when volatile oils, phenol/choral hydrate added
- Suppositories more difficult to administer as theobroma oil melts on the fingertip
- Tends to leak out of the orifice –> can be messy if the patient needs to stand up and move around
8
Q
What are the types of suppository bases:
A
- Oleaginous bases
- Water-soluble/water-miscible (Glycerinated gelatin, polyethylene glycols)
- Emulsifying bases
9
Q
what are the two types of gelatin commonly used and what are they used with?
A
- Pharmagel A: Cationic, incompatible with anionic compounds
- Pharmagel B: Anionic, incompatible with cationic compounds
10
Q
Advantages of glycerinated gelatin base
A
- More prolonged drug release –> commonly used in pessaries
- More easily inserted –> suitable for urethral administration
- Does not melt on fingertips
11
Q
Disadvantages of glycerinated gelatin base
A
- Hygroscopic –> dehydrating effect on mucous membrane
2. Supports growth of mould
12
Q
Advantages of PEG bases
A
- Bases with higher melting points can be formulated
- Convenient storage and do not have to be refrigerated
- Easy insertion
- No leakage from orifice
- Control drug release as bases of varying solubilities can be formulated
13
Q
Disadvantages of PEG bases
A
- Incompatible with phenols
2. Hygroscopic
14
Q
What are emulsifying bases?
A
Bases usually composed of triglycerides with 1 or more emulsifying agents
15
Q
Advantages of emulsifying bases:
A
- Not adversely affected by overheating
- Solidify rapidly at RTP –> can be produced quickly
- Do not adhere to mould
- Non-irritating
16
Q
Disadvantages of emulsifying bases:
A
- Not suitable when rapid drug release required
2. Do not melt and dissolve rapidly in rectum
17
Q
What are some types of packaging used to pack suppositories?
A
- Partitioned boxes
- Screw-capped
- Glass/plastic containers
- Aluminium foil wrappings
- Disposable plastic moulds
18
Q
Describe the hot process used to prepare suppositories
A
- Base melted over hot water bath
- Molten mixture poured into lubricated mould and allowed to set in the cold
- Suppositories formed are removed from metal moulds/ supplied in disposable moulds
19
Q
Describe the two different types of cold processes
A
- Hand moulding: base thoroughly kneaded with drug, rolled into thin cylinder of uniform diameter then cut into individual which are hand moulded into desired shape
- Compression moulding: Base thoroughly kneaded with drug and then filled into cylinder and compressed in the compressing machine
20
Q
components to evaluate suppositories:
A
- Appearance (color, surface condition, shape, uniformity of mix)
- Uniformity of weight (uniformity of drug content)
- Disintegration time
- Drug release profile
- Mechanical strength
- Melting behaviour
(2 and 3 are BP requirements)
21
Q
How to test for uniformity of weight, and what is the acceptance criteria?
A
- Take 20 suppositories at random from the batch
- Weigh suppositories individually
- Calculate average weight
- Acceptance criteria: ≤2 individual weight deviate from average weight by >5% and none deviated from >10%
- Test not required for moulded suppositories required to comply with test for uniformity of drug content
22
Q
Test for uniformity of drug content:
A
Drug extracted from base and assayed using appropriate methods –> content critical for those that are highly potent
23
Q
Describe the test method to assess the disintegration time for suppositories
A
- Apparatus put into vessel containing at least 4L of water at 36-37ºC and fitted with slow stirrer
- apparatus inverted every 10 mins in liquid medium and take out at the designated time to check if it has disintegrated
- disintegration test carried out on 3 suppositories separately
24
Q
Interpretation of disintegration test results, and the acceptance criteria
A
Disintegration complete only when any one of the following occurs:
- Completely dissolved
- Dispersed into components parts
- Suppository has become soft and the mass has no solid core –> no resistance to pressure with glass rod
Acceptance criteria:
- Fat-based ≤30 min
- Water-soluble ≤60 min
To pass test, all 3 suppositories tested should satisfy criteria
25
Describe the test carried out to determine the drug release profile of a suppository
Obtained by determining amount of drug released from suppository to external medium over time
- Basket/paddle method （Slide32)
- Aliquot samples of dissolution medium withdrawn at specific time intervals for drug assay
- Release profile should match what the manufacturer claims
26
Describe the test method used to determine mechanical strength of suppositories
Determined with apparatus --> test amount of stress suppository can withstand (Slide 34)
27
What are the two parameters to take note of when testing a suppository for its melting behaviour?
1. Softening temperature: Temperature at which deformation occurs, indicating the ease of insertion and physical stability of suppository during handling
2. Liquefaction temperature: Temperature at which suppository melts, affecting drug release and test only necessary for suppositories with oleaginous bases (slide 36)
28
Physiochemical factors affecting PK and PD of the drug contained inside a suppository
Chemical composition of base, viscosity of base, interaction between base and drug, partition coefficient of drug between base and rectal fluid,
drug particle size, charges on drug molecules, lipid solubility of drug, surface property of drug, amount of drug, effects of suppository on rectum/mucous membrane
(think of what must happen when suppository is inserted)
29
Properties of base to be considered in formulation:
1. Stability
2. Compatibility with other components
3. Viscosity of molten base
4. Rate of drug release
5. Temp. range between melting and solidification
6. Volume of contraction
7. Brittleness
8. Hygroscopicity
30
Properties of drugs to be considered in formulation:
1. Solubility
2. Particle size
3. Surface property
4. Displacement value
31
BP formula for glycerinated gelatin is:
- 4-18% gelatin
- 70% glycerin
- 12-26% water
What are the functions of gelatin and glycerin?
- Gelatin: Impart hardness to the base
| - Glycerin: Impart hydrophilicity, so that the base can attract water
32
A simple solution that one can adopt to minimise stinging sensation to the orifice when glycerinated gelatin based suppository is administered
Moisten the suppository with water before insertion
33
Macrogol bases are formulated with a mixture of PEG with varying MW. How do some properties of the base vary as MW increase?
1. Hardness increase
| 2. Melting point increase (may even be used for drugs that lower the melting point of the base)
34
One possible issue of making suppositories using compression moulding method
Air may be trapped in the suppositories, making them underweight
35
What type of packaging are most suitable for suppositories that may stick to each other?
1. Partitioned boxes
| 2. Aluminium foil wrappings
36
Theobroma oil shows "bloom" upon storage. Explain what and how "bloom" arises, and whether is it a problem
- "Bloom" is when white powdery deposits on the surface of the suppository
- Unstable forms of theobroma oil forms and migrates to the surface of the suppository due to temperature fluctuation
- Suppositories still can be used
37
What is a potential problem on storage of fat base?
Elevated melting point
- Caused by more stable form of fat base forming over time
- This can reduce drug release rate as it is more difficult for fat base to melt
38
What is the displacement value of a drug in the formulation of suppositories?
It is the number of parts by weight of a drug which displaces one part by weight of base
39
A suppository containing 0.5g of ZnO is to be prepared using theobroma oil and a mould of 1g theobroma oil capacity. The displacement value of ZnO = 5. What is the weight of theobroma oil required per suppository?
0.5g of ZnO displaces 0.5/5 = 0.1g of theobroma oil
Hence weight of theobroma oil required per suppository = 1 - 0.1
= 0.90g
40
Once an Oleaginous base suppository is inserted into rectum, what are the processes that occurs before the drug diffuses into the mucosal lining?
1. Melting of base
2. Sedimentation of drug particle
3. Wetting of drug particle on mucosa lining
4. Dissolution of drug particle
41
Describe how do drugs inside a suppository made of water-soluble or emulsifying base enter the systemic circulation
- Those bases do not melt in rectum
- They dissolve and disperse very quickly into rectal fluid
- Once base is dissolved and dispersed, solid drug particles are released from base, gradually dissolve and diffuse through mucous lining into the systemic circulation
42
Describe what happens to soluble drug particles inside a suppository when the suppository is inserted into the rectum
The drug particles diffuse through the molten base then penetrate immediately through the mucous membrane
- NO sedimentation, wetting and dissolution
Form & Tech II
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